Non Small Cell Lung Cancer

Non Small Cell Lung Cancer
Moderator : Dr. R. Kapoor

Introduction
• Most common malignancy in males around

the world.
• Leading cause of cancer related mortality.
• Lung cancer recently surpassed heart
disease as the leading cause of smoking-
related mortality!
• In India accounts for the commonest
cancer in 3 leading cancer registries –
Bhopal, Delhi & Mumbai.
Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Anatomy

Bronchopulmonary segments
• Independent anatomical &

functional subunits of lungs
• Number: 10 in each lung
• Each segment has a
centrally located:
– Segmental bronchus
– Segmental branch of
pulmonary artery
– Segmental branch of
bronchial artery
• The pulmonary veins and
lymphatics are
intersegmental in position.
• Early malignant pathology is
usually confined to the
segment from which it
originates.

Lymphatic Drainage
Level 1: Highest Mediastinal nodes

Level 2: Upper paratracheal nodes
Level 4: Lower paratracheal nodes
Level 10: Hilar nodes
Level 11: Interlobar nodes
Level 12, 13, 14: Lobar, segmental &

subsegmental nodes
Level 7: Subcarinal nodes nodes
Level 8: Paraesophageal nodes

Level 9: Pulmonary ligament nodes

Lymphatic Drainage
Level 3A and 3P: Prevascular and

retrotracheal nodes
Level 6: Paraaortic nodes
Level 5: Subaortic nodes

Classification &
Pathology
Pathology
Primary Lung Cancer
Non Small cell type (70% - 80%) Small Cell type (20% – 30%)
Bronchial surface epithelial type

Squamous cell (30 - 50%)
Goblet cell type
Adenocarcinoma (20 - 40%)
Clara cell type
Large Cell (10 – 15%) Type II alveolar cell type
Adenosquamous Bronchial gland type
Carcinomas with sarcomatous elements
Neuroendocrine
Others

Squamous cell carcinoma
Squamous cell Carcinomas

• Arise centrally within the main,
lobar, segmental or
subsegmental bronchi.
• Extends into the lumen of the
airway with invasion into the
underlying wall.
• Because there is exfoliation of the
malignant cells from the
bronchial surface, squamous cell
carcinoma can be detected by
cytologic examination at its
earliest stage.
• Tend to be slow growing.
• Incidence of SCC appears to be
decreasing relative to
adenocarcinoma.

Adenocarcinoma
Adenocarcinoma
• Usually arise in the smaller
peripheral airways (as distinct
from the cartilage bearing
bronchi).
• Detected earlier by radiology.
• Most common in non-smokers
and women.
• Rising incidence associated with
different pattern of tobacco
consumption.
• More frequently associated with
pleural effusions and distant
metastases.
• Premalignant leison is known as
atypical alveolar hyperplasia.

Special types
Bronchoalveolar carcinoma
– Considered as precursor leison to
invasive adenocarcinoma.
– Growth along pre-existing alveolar
structures without evidences of
stromal, pleural, or vascular
invasion and without metastasis
(lepidic growth pattern).
– Right to left intrapulmonary shunt
due to impaired gas exchange.
– Origin: Surfactant secreting Clara
cells ?

Risk Factors
• Smoking
• Genetic predisposition
– Genetic trait : Li Fraumeni syndrome (P53 mutation)
– Gene polymorphisms:
• DNA repair genes : XRCC1
• COX 2
• Interleukin 6
• Occupational & Environmental exposure
– Asbestos exposure: Occupational or residential (silicate type fibers)
– Foundry workers and welders: Ni, Co, Cd
– Uranium mine workers: Inhaled Radon
– Air pollution:
• Diesel exhaust
• Metal fumes
• Air sulfate and PAH content
• Dietary influence
– Folate & B12 deficiency
– Inadequate antioxidant consumption

Smoking: Association
• Incidence trends reveal a matching rise and
A cigarette
``fall with changesis
in a euphemism
smoking habits. for a
• Rising trend in women correlates with rising
cleverly
incidence crafted
of smoking product that
in them
• delivers just the
Persistent smoking wasright amount
associated of
with a 16-
fold increase in cumulative lung cancer risk
• nicotine to keep
Risk is doubled its user
if smoking addicted
commenced before
age 15.
•
for life before killing the person.''
Duration and intensity are both correlated the
former in a exponential fashion.
•World Health
Cancer risk Organization director-general
declines substantially Gro
after cessation.
• Even passive smoking
Harlem is associated with an
Brundtland
increased risk (25%)
• China has the largest number of young smokers
in the world and the highest incidence!
• Use of filter cigarettes has been correlated with
peripheral carcinogen deposition and association
with adenocarcinoma.

Pathogenesis: Squamous type

Pathogenesis: Adenocarcinoma

Presentation
Incidence & Prevalence
Incidence per 100,000
3.8
India
12.1
26.6
China
67.5
13.3
Japan
44.6
12.9 120
Sweden
22
100
22 80
UK
51.2
60
33.5 40
USA
55.7 20
0
0 20 40 60 80
1974
1976
1984
1986
1988
1992
1994
1996
2000
2002
1978
1980
1982
1990
1998
Males Females
Male Female

Symptoms
Cough
Hemoptysis
Central growth
Dyspnea / Wheeze
Pneumonitis
Pain
Symptoms
Cough
Peripheral growth
Dyspnea
Hoarseness
Lung abscess
Dysphagia
Diaphragmatic palsy
Horner’s Syndrome
Regional Spread
SVC syndrome
Pancoast syndrome

Signs
SIADH
• Signs directly caused by tumor
invasion or compression: Cushing’s Syndrome
– Limitation of chest movement Carcinoid Syndrome

– Rib tenderness Gynecomastia
– Vocal cord palsy Cerebellar degeneration
– Horner’s syndrome Eaton Lambert syndrome
– Engorged veins in the chest Autonomic neuropathy
wall and face
Optic neuritis
• Signs due to metastasis
Pure red cell aplasia
– Bony tenderness
DIC
– Adrenal insufficiency
– Organomegaly Anemia, thrombocytopenia
• Paraneoplastic syndromes: Acanthosis nigricans
– Cancer cachexia (MC) Hyperkeratosis

– Hypercalcemia Hypertrichosis
– HPOA & clubbing VIP induced diarrhea
Hyperamylesmia

Investigations
• Investigations to confirm the disease

– Sputum cytology (sensitivity 65% - 75%)
– Transthoracic FNAC (sensitivity 87% - 91%)
– Bronchoscopic biopsy (70% - 80%)
– TT-FNAC associated with
• Pneumothorax (27%)
• Hemoptysis (5%)
• Local bleeding (11%)
• Investigations to assess the stage
– Imaging
– Bronchoscopy
– Mediastinoscopy
– VATS
• Investigations to assess fitness for treatment
– Hemogram
– Renal and liver function tests
– Pulmonary function tests

Chest X ray

Imaging
• Plain X rays
– A tumor visible in a chest X ray has usually completed 75% of
it’s natural history.
– Guides local radiotherapy
– Cheap follow-up assessment
• CT scans:
– Accurate assessment of primary disease.
– Best for detection of mediastinal and chest wall invasion.
• Nodal size < 1 cm : 8% chance of occult nodal metastasis
• Nodal size > 2 cm : 70% chance of occult or overt metastasis
– Assessment of abdominal disease esp. of adrenal involvement.
– Various nodal size criteria exist to predict likelihood of nodal
mets.
– Pitfall: Pneumonitis cant be accurately distinguished.
• PET CT has a greater degree of sensitivity for detection of
nodal disease that would be missed by size based criteria
alone.

Bronchoscopy
Most valuable invasive investigation as it allows:

– Confirmation of diagnosis:
• Biopsy and brushings 80% accurate
• Low false positive rates 0.8%
• Transbronchial forceps biopsy positive in 70%
• Visualization of tumor done in 60% - 75%
– Staging of the tumor:
• Extent of bronchial and carinal involvement.
– Symptom alleviation:
• Stenting
• Bleeding control
• Importance in brachytherapy
– Response assessment
– Detection of preinvasive malignancy (screening):
• Autoflurosecence bronchoscopy.

Staging & Prognosis
Staging
• T1:
– 3 cm or less,
completely covered by
pleura, does not involve
main bronchus

Staging
• T2:
– > 3cm size.
– Visceral pleura
involved.
– Main bronchus invasion
but > 2cm from carina.
– Atelectasis / obstructive
pneumonitis that
extends to the hilar
region but does not
involve the entire lung.

Staging
• T3:
– Chest wall
– Diaphragm
– Mediastinal pleura
– Pericardium
– Main bronchus <2cm to
carina
– Complete atelectasis /
obstructive pneumonitis
of entire lung

Staging
• T4:
– Carina
– Vertebrae
– Great Vessel
– Esophagus
– Heart
– Separate tumour
nodule in same lobe
– MALIGNANT pleural /
pericardial effusion

Staging
• N0:
– No regional LN metastases
• N1:
– LN mets in ipsilateral
peribronchial and/or
intrapulmonary (Levels
10, 11, 12, 13, 14)
• N2:
– Ipsilateral mediastinal or
subcarinal
• N3:
– Contralateral mediastinal
/hilar
– Ipsilateral or contralateral
supraclavicular/ scalene
nodes

Staging: AJCC 2002
5 yr overall survival
Stage TNM 80%
T N M
70%
IA T1 N0 M0 67%
60%
IB T2 N0 M0
55%
IIA T1 N1 M0 50% 55%
45%
IIB T2 N1 M0
40%
T3 N0 M0
30%
IIIA T3 N1 M0
22.50%
T1-T3 N2 M0 20%
IIIB T4 N0-N2 M0 10% 2.50%

7.50%
T1-T4 N3 M0
0%
IV T1-T4 N0-N3 M1
IA IB IIA IIB IIIA IIIB IV

Staging Controversies
• Tumor size cutoff of 3 cm.

– Several authors have demonstrated the prognostic value of size
> 5 cm and recommend it be incorporated in T3 disease.
• T3N0M0 is lumped into stage IIB
– Prognosis of patients with chest wall disease significantly better
than other T3 category tumors even after complete resection.
– Even those T3 patients who have rib destruction have a
significantly poorer prognosis as compared to those with soft
tissue involvement.
– Depth of invasion another important variable that is ignored.
– Tumors invading the vagus or phrenic nerves have prognosis
similar to stage IIIB patients!
• Normal lymphatic drainage of the lung doesn't obey
the midline!
– Right sided lymphatics extend to the left border of the trachea
across the midline.
– Survival of patients with level 3 and 7 nodal involvement is
markedly poorer.

Adverse Prognostic Factors
• Age > 65
• Performance status > 2
• Advanced stage
• Presence of mediastinal lymphadenopathy
• Tumor hypercalcemia
• Surgical procedure : Limited resection
• Positive resection margins
• Biological markers:
– COX 2
– p 53
– EGFR
– erbB2

Prevention & Screening
• The most cost effective method of lung cancer prevention is to stop
smoking.
– Chemoprevention strategies in primary and secondary lung cancers have
not been fruitful.
– Addition of β carotene actually increased incidence & mortality in
patients with high risk factors e.g. smoking.
CARET trial and ATBC lung cancer prevention trials.
• Screening of lung cancer was initiated with CXR and sputum
cytology
• Disadvantages:
– Early detection failed to improve prognosis even in high risk groups.
– False positive results may be as high as 5% in CXR
– Both are relatively insensitive to early stages.
– The prevalence in the population is not high enough to justify routine
mass screening.
• 3 major randomized trials have failed to provide evidence of any
benefit from screening.
• In USA non-contrast spiral CT is being evaluated as a screening tool
in the high risk group.

Surgery
Surgery : Types
• Radical operation:
– Pneumonectomy.
• Lung Conservation:
– Lobectomy.
– Sleeve resection.
– Wedge resection.
– Segmentectomy.
• Mediastinal lymph node
dissection:
– Provides complete nodal
staging.
– Identifies patients who require
adjuvant radiotherapy.
– Improves survival.
– Improves local control.
• At least nodal sampling should
be performed, if not complete
lymphadenectomy.

Lymph node dissection
• Lobe specific
mediastinal nodal
dissection in NSCLC:
– Right Side:
• Upper lobe (1,2,3,4,7)
• Middle lobe (1,2,3,4,7)
• Lower lobe (1,2,3,4,7,8,9)
– Left Side:
• Upper lobe (4,5,6,7)
• Lower lobe (4,5,67,8,9)

Complete Resection
• Free resection margins proved

microscopically
• At least a lobe specific mediastinal
nodal dissection with complete hilar and
intrapulmonary nodal dissection.
• At least 6 nodes should have been
removed with 3 from mediastinal nodes.
• No extracapsular extension in the nodes.
• Highest mediastinal node removed should
be microscopically free.
Ramon et al Lung Cancer (2005) 49, 25—33

Surgery : PFT based algorithm
Surgery Type
Lobectomy /Lesser Pneumonectomy
FEV1 > 1.5 L FEV1 > 2 L

FEV1> 60% FEV1> 60%
DLCO > 60% DLCO > 60%
Operate •V/Q scan Operate

•Calculated Post operative FEV1 & DLCO
< 40% > 40%
Exercise study
Average risk
V02 max < 15 ml/kg/min V02 max > 15 ml/kg/min
Medically inoperable

Criteria for inoperability
• Tumor based criteria:

– Cytologically positive effusions.
– Vertebral body invasion.
– Invasion or in casement of great vessels.
– Extensive involvement of Carina or trachea.
– Recurrent laryngeal nerve paralysis.
– Extensive mediastinal lymph node metastasis.
– Extensive N2 or any N3 disease.

Results
• T1 tumors: • Morbidity:
– Five-year overall – 15% reduction in
survival: 82%. spirometric values in
– 10 year overall lobectomy
survival: 74%. – 35% - 45% reduction
after pneumonectomy.
• T2 tumors:
• Mortality:
– Five-year overall
survival: 68%. – 7% perioperative
mortality for
– 10 year overall
pneumonectomy.
survival: 60%
– 4% perioperative
mortality for lobectomy

Patterns of failure
• In stage I tumors:
– Local recurrence rate = 7%
– Distant failure rate = 20%
– Second primary cancer = 34%
Martini et al, J Thor Cardiov Surg 1995; 109: 95 – 110.
• In stage II / III tumors:
– Intrathoracic failure rate: 31%
Ludwig lung cancer study group. Ann Surg 1987; 250: 67 – 71.
– 5 survival in clinical N2 negative nodes: 27%
– 5 survival in clinical N2 positive nodes : 8%
Martin et al. Ann Surg 1983; 198 (3): 386 – 97.
– Tumors measuring 1-2 cm have a mediastinal nodal metastasis
rate of 17% as compared to those measuring 2 to 3 cm, when
the rate is 37%!
• Patients who fail after surgery, present with extrathoracic
disease 70% of the time, local recurrence in 20% and
local and distant metastasis in 10%.
• 2nd primary lung cancers are known to occur at a rate of
1% per year in survivors.

Radiotherapy
Role of Radiotherapy
• Plays an important role in the management of

approx 85% of patients with non small cell lung
cancers.
• RT can be applied in the following settings:
– With curative intent
– With Palliative intent
• RT is the most common treatment modality in
majority of patients in India as:
– Majority of the patients present with hilar or mediastinal
disease.
– Disease bulk prevents the use of surgical techniques.
– Surgical oncology facilities are not available widely.
– Associated comorbidities and poor lung function make
patients not suitable for surgery.
– Advanced age and poor socioeconomic status make RT an
attractive treatment option.

Treatment techniques
• Treatment for cure

– As definitive treatment alone (or with chemotherapy).
– As adjuvant treatment post surgery.
• Treatment for local control with limited
probability of survival.
• Treatment for relief of symptoms, when the
disease is too locoregionally advanced for control.
• Treatment in special situations:
– Treatment for superior sulcus tumors.
– Treatment for SVCO.
– Local palliative treatment
– Brachytherapy.

Curative radiotherapy
• Indications for curative • Contraindications for

definitive radiotherapy: curative definitive
– Histologically proven radiotherapy are:
squamous cell carcinoma. – SVC syndrome.
– Medically inoperable – Paralysis of recurrent
patients with localised laryngeal nerve.
tumors. – Paralysis of phrenic nerve.
– Unimpaired functional – Pleural or pericardial
status with or without effusions.
symptoms (WHO < 2).
– Extensive infection
– Weight loss lesser than including abscess
6%. formation
– No evidence of distant – Destructive involvement of
metastasis. chest wall.
– Superior sulcus tumors

Technique
• Patients should be treated in supine position

unless indicated otherwise.
• Dose: 60 Gy in 30 # over 6 weeks
• Both cobalt or LINAC can be used with equal
efficacy.
• Energy range is choosen to be 6 – 10 MV
• Lung correction factor should be applied during
the calculations especially if manual calculation is
being done.
– Co60 & 4MV  4% per cm of lung tissue
– 10 MV  2% per cm of lung tissue
– 20 MV  1% per cm lung tissue

Field Selection
• Parallel opposed anterior and posterior
fields are used.
• The primary disease should be
encompassed with the 2 cm margin of
normal-appearing lung.
• In upper and middle lobe or hilar
disease, the inferior margin is situated
5 to 6 cm below the carina.
• In upper lobar disease the superior
margin should cover the ipsilateral
supraclavicular fossa.
• In lower lobe disease, inferior margin
extends to the vertebral origin of the
diaphragm.
• Width of the mediastinal field
encompasses the vascular shadow, or
the lymphadenopathy, whichever is
wider.
• Field margins should be such that, the
tumor lies within the field during
inspiration and expiration.

Advanced techniques
• Recent innovations
– 3 DCRT
– IMRT
– IGRT
• Respiratory gating:
– Tumors in lung may move by as much as 5-10 mm
during normal quiet breathing.
– The PTV may be effectively doubled if this is taken into
account  dose escalation impossible
– Two techniques of respiratory gating are:
• Breathhold techniques:
– Active : Using valves and spirometers
– Passive: Voluntary breath holding (used in PGI)
• Synchronized gating technique : Uses free breathing with
synchronized beam delivery.

IMRT : Institutional example

IMRT : Institutional example
PTV
Esophagus
Spinal Cord

Results
• Till date phase I / II trials available for

3DCRT
• 3 yr overall survival in early stage I/II
disease 29% (Hayman et al).
• 50 -60% patients still fail at distant sites.

Problems of IMRT in lung
 Suitability of patients for curative radiation therapy.

 High incidence of mediastinal nodal involvement even in
stage I tumors.
 Complex tumor movement with breathing and cardiac cycle.
 Difficulty in assessing proper CTV – Is it pneumonitis or
tumor?
 Intrinsic radiation sensitivity of the lungs and poor
pretreatment lung function.
 Inability to include the mediastinum if dose escalation is
desired.
 Lack of clinically validated predictors of lung toxicity in IMRT
with its characteristic inhomogeneous dosage.
According to AAPM & ASCO IMRT in lung tumors should
not be considered outside research settings at
present.

Results: Stage I
Intercurrent
Authors Dose % T1 3 yr OS 3 yr CSS
death
Kaskowitz et al 63 Gy (Median) 38% 19% 33% 27%
Krol et al 60 – 65 Gy 47% 31% 42% 34%
Sandler et al 60 Gy (Median) 32% 17% 22% 16%
Sibley et al 64 Gy (Median) 54% 24% - 43%
Talton et al 60 Gy 3% 21% - -
Noordijk et al 60 Gy 50% 33% - 40%
• Comparison for crude survival data presented by

Fletcher et al reveals the 3 year survival rate of
10% in less advanced tumors.
• Presently patients with T1 tumors can expect a 3 yr
actuarial survival probability in the range of 20% -
30%.

Patterns of failure: Early stage
• Definitive RT alone results in local failure in

33% -45% patients.
• Lower doses (40Gy) result in local failure in
44% - 50% patients.
• LeChevalier et al have reported 83%
-85% pathological local failure rates in
patients treated with dose of 65 Gy.
• Incidence of distant mets 75% -80%
• Local tumor control however yields a
significantly better survival (22%) at 3 yrs
as compared to local failure (10%).
Perez et al IJROBP 1986;12:539 – 47

Better Surgical results: Why?
• As a curative modality radiotherapy fares poorly in

studies as:
– Most patients excluded from surgical series have serious
medical comorbidities.
– Pathological staging is not done  37% upstaging by
pathological staging can be the reason for stage wise
better survival in lung cancer in surgical series.
– Both modalities are for local control and surgery results in
quicker and more through eradication of a small localised
disease.
– Consideration of long term and short term toxicity result
in the inability to deliver an actual curative dose in RT
trials.
– The mobility of these tumors may be another reason for
their apparent poorer result.

RT: Advanced Disease
• Aim: • Aim:
– To achieve local – To achieve relief of
control due to high symptoms only when
probability of death due disease is too advanced
to progression of for local control
systemic disease. • Indications:
• Indications: – T4 disease
– T3 disease – Extensive N2 or N3
– N1 or small N2 disease disease
– No evidence of distant – Distant metastasis
metastasis – Weight loss > 12% of
– Weight loss < 12% of body weight
body weight – > 50% of normal
– < 50% of normal working time spend in
working time spend in bed.
bed.

Technique
For local control where patient is expected to die of

systemic disease:
– ~ 60-80% patients die from distant metastasis in this
subgroup making radical treatment futile.
– Supraclavicular fossa should be incorporated if involved or
in upper lobar tumors.
– Usually a dose of 30Gy in 15# over 3 weeks is followed
by 2-3 weeks gap. Further therapy is then individualized.
– 20 Gy in 10# is given in the second course over 1 week.
– In certain selected situations 30 Gy / 10# in 2 weeks
may be prescribed in the event of a very good response
and good GC.

Technique
• For symptom palliation the dose and

fractionation is tailored to the condition
depending upon the life expectancy:
– Treatment schedules choosen:
• If life expectancy is > 3-4 months : 30 Gy in 10#
over 2 weeks
• If life expectancy is from days to 3 months :
– 20 Gy in 5# over 1 week
– 8 Gy in single fraction.
– 1st schedule better as option for a 2nd course
kept open if needed.

Why a Split Course?
• Majority of our patients are treated with a split

course as:
– Disease is too advanced at presentation to attempt a
cure.
– Allows healing of acute toxicity in between two courses.
– The split allows the patient to return home and thus is
more comfortable for the patient.
– Response evaluation may be done at the beginning of
the second course allowing further treatment selection.
– We can give simultaneous treatment for any bone or
brain mets that the patient may develop during the
second course.
– The theoretical fear of tumor repopulation leading to local
failure during the gap is offset by the limited life span and
higher probability of death from distant metastasis in
these patients.

RT results: Split Course
• Split course RT is criticized due to 45%

the radiobiological claim of tumor
repopulation during the break. 40%
• However in two randomized
35%
studies by Holsti et al (1980) and
Lee et al (1976) no survival 30%
advantage of continuous course
RT could be demonstrated. 25%
• In another series by Perez et al
(RTOG 73-01), the survival for 20%
patients receiving split course
was comparable after 4 years 15%
to those receiving a continuous
regimen (stage I/II). 10%
• However they also reported a 5%
lower in field control rate for
split course regimen. 0%
1 yr 2 yr 3 yr 4 yr
Continous Split Course

Special Situations
SVC Syndrome Symptomatic Relief from SVC

• Patient should be started on Syndrome after RT
decongestive measures prior to
starting radiotherapy.
– I/V steroids
– Moist Oxygen 15%
– Bronchodilators 15%
• RT induced edema can
exacerbate symptoms in the 50%
first few days 20%
• Doses will depend upon the GC

of the patient.
• Usual doses:
– 30 Gy in 10# in 2 weeks
– 20 Gy in 5 # in 1 week Excellent Good
– 8 Gy in SF Minimal No response
• Regimen selected depends on

patient age and GC.

Superior Sulcus Tumors
• In patients with painful

apical syndrome only:
– 30 Gy / 10 #
– Superior border kept at C5
level
– Inferior border 5 cm below
carina
– Laterally include the full width
of the upper 4 ribs.
– Medially entire mediastium.
• Pt should be assessed for
possible Sx after this
course.
• The contraindications for
Sx are mentioned later on.
SST: Results
• Preoperative RT:
– 50% - 60% become operable after preoperative RT.
– 5 yr Survival in this group was 30% - 40% which was
better than the group who couldn't undergo operation.
– Martini et al found that preoperative RT also improved the
complete resectability rates (from 9% to 40%).
• Postoperative RT:
– Like in other situations no survival benefit has been
found.
– However difficulty in obtaining clear resection margins
make post operative RT necessary with an aim to improve
local control.

Inoperable SST
• Surgery is 100%
contraindicated 90%
in patients with: 80%

– Horner’s Syndrome
– Rib destruction 70%
– Brachial plexus 60%

involvement.
50%
– Major vessel
involvement. 40%
• Treatment goal is 30%

palliation of 20%
symptoms.
• RT/CCT are the 10%
main therapeutic 0%
modalities. Pain relief Horner's

Syndrome
3 yr Survival

Dose Intensification
• Rationale: Adding to local control in early disease adds to a

survival advantage.
• Premise: Intensification of dose in temporal or quantitative
fashion will translate into a better local control.
• Basic data: (Fletcher et al) Dose required for eradication of
malignant squamous cell lung cancer encountered usually
varies from 80 – 100 Gy.
• Implication: We should be in the steep portion of the dose
response curve with a steep rise in local control with a small
increase in dose.
• Problem: High radiation sensitivity of lungs and
surrounding normal tissue and the high incidence of death
from systemic disease.
• Modalities:
– Hyperfractionation
– Chemoradiation
– Conformal avoidance

Hyperfractionation
• Aims to keep the dose per fraction low to avoid toxicity while
giving a number of fractions per day to exploit the
differential repair kinetics of malignant and normal cells.
• In two trials by Arrigada et al and Sause et al no survival
benefit could be demonstrated over conventional
fractionation.
• Further no benefit of dose escalation over 69.6 Gy could be
appreciated in terms of local control or survival.
• Hyperfractionated accelerated radiotherapy (HART) in stage
IIIA and IIIB patients has been evaluated by a phase II
ECOG study.
• The results were:
– Median relapse free survival: 7 months
– 1 year relapse free survival: 23%
– Grade 3 acute toxicity: 30%

CHART & CHARTWEL
• CHART is a variant where 54 Gy were delivered in

1.5 Gy / # thrice daily over 12 continuous days.
• Results:
– 2 year survival 29% (Control – 20%)
– Local control 23% (Control – 15%)
– Acute radiation pneumonitis 10% (Control 19%)
– Severe esophagitis 19% (Control 3%)
– Late pulmonary fibrosis requiring treatment 16% (Control
4%)
Saunders et al. Radiotherapy and Oncology 1999;52:137-148
• New modality : CHARTWEL

Chemoradiation
• Administration of chemotherapy
concurrently with radiation therapy
theoretically improves local control by
sensitizing the tumor to radiation, while
simultaneously treating systemic disease,
albeit at the expense of greater local
toxicity.

Sequential CCT +RT : Results
Author Regimen N Median Survival 3 yr OS
Dilman et al RT (60) 77 9.7 mo 11%
(CALGB) PV  RT (60) 79 13.8 mo 23%
Sause et al RT (60) 149 11.4 mo 6%
(RTOG 88-08) PV  RT (60) 151 13.2 mo 15%
RT (69.6) 152 12 mo 13%
LeChevalier RT (65) 177 10 4%
VCPC  RT  VCPC 176 12 12%
• A metaanalysis by the Institut Gustave-Roussy and the British

Medical Research Council Cancer Trials Office showed a
statistically significant, overall benefit with chemotherapy.
• The overall hazard ratio (HR) was 0.90 (p = 0.006)
• The absolute survival benefit was 3 per cent at 2 years and 2
per cent at 5 years!

Concomitant CCT +RT : Results
Author Regimen N Median Survival 2 yr OS
Soressi et al RT (50) 50 11 mo 25%
P+ RT (50) 45 16 mo 40%
Blanke et al RT (60 -65) 111 11.5 mo 13%
P  RT (60-65) 104 10.6 mo 18%
Shaake- RT (55) 108 - 13%
Koning et al P + RT (55) 98 - 19%
(EORTC)
P (daily) + RT (55) 102 - 26%
Jeremic et al RT (64.8 , HF) 61 8 6.6%
PE** + (64.8 , HF) 56 13 16%
PE** (daily) +(64.8 , HF) 52 18 21%
**Carboplatin and etoposide
• In the RTOG 9401 trial a concurrent CCT + RT approach resulted in

improvement of survival from 14.6 to 17.1 months as compared to
sequential approach. Other authors have also corroborated these
results ( Furuse et al, Zatloukal et al).

Recommendations
• Useful in patients with good general condition

and performance status only.
• Single agent CCT is no better than radiation
alone when used sequentially.
• Should be using a platinum based regimen as
other regimens have not resulted in an improved
survival (Pujol et al).
• Concurrent CCT is better than sequential but
also leads to a greater toxicity (RTOG 9401 results).
• Higher levels of hematotoxicity should be
anticipated before hand.
• Should be reserved for the trial setting because
of the toxicity may not be routinely manageable.

PGI results
• Protocol: Cisplatin 30 mg/m2 weekly with

50 Gy/25# vs RT 50 Gy/25# alone
• Despite the limited patient numbers the
points emerging were:
– Patients had symptom severity similar to the
palliative patients in the Langendijk study
– Symptom control was not different.
– Significantly more dysphagia in chemoradiation
arm
– Paradoxically CR was lesser in the
chemoradiation arm (? Less patients completing
treatment due to toxicity)

Postoperative Radiotherapy
• Indications:
– Advanced disease:
• Margin positive (< 0.5 cm)
• Microscopic or macroscopic residual disease
• Hilar or mediastinal node positivity
• Mediastinal or chest wall invasion.
• Dose : 30 – 40 Gy in 10-20 # over 2 weeks.
• Why is data regarding PORT inadequate?
– Unlike surgical series none of the studies have taken into
account the extent and site of nodal involvement which
have been found to be important prognostic variables.
– Many studies reported used inadequate doses and
improper fractionation and were conducted in the
orthovoltage era.

Results
• Early Stage Disease post complete resection and

node negative RT should be avoided as:
– Most patients die of systemic disease.
– Local control is excellent with surgery alone.
– Added toxicity dilutes any survival benefits.
» Van Houtte et al. IJROBP 1980; 6:983 – 86
» PORT Meta-analysis Trialists Group. Lancet 1998;352:257
• Negative surgical margins and positive

mediastinal nodes
– Reduction in local recurrence was found in two major
trials from 41% to 3%
– Patients with N2 disease experience better local control,
survival and less distant mets but no advantage in N1
disease
» Stephens RJ. Br J Cancer 1996;74:632.
– No benefit as far as overall survival is concerned.
» LCSG. N Engl J Med 1986; 315 : 1377 – 81

Preoperative radiotherapy
• Preoperative irradiation was occasionally used in selected

patients to:
– Reduce the bulk of tumor.
– Take care of subclinical spread beyond the surgical margins.
– Prevent dissemination by surgical manipulation.
– Use lower doses of radiation than those required
postoperatively.
• However preoperative RT is no longer recommended as:
– Leads to unnecessary treatment delay.
– If surgical resection is not feasible, then efficacy of further
radiation is lowered.
• Both randomized and nonrandomized data indicate that
preoperative radiation alone does not improve the long-
term survival
– 5 year survival rate was 14% after preoperative radiotherapy
and 16% after immediate surgery
Warram J, Preoperative irradiation of cancer of the lung: final report of a
therapeutic trial. A collaborative study, Cancer. 1975 Sep;36(3):914-25.

Radiotherapy: Toxicity
TD 5/5 Volumes & Tolerance (Gy)
• The most common and
significant radiation Organ 1/3 2/3 3/3
toxicity is radiation Lung 45 30 17.5
pneumonitis. Heart 60 45 40
• Occurs in two forms: Esophagus 60 58 55
– Acute (1-6 months). Spinal cord 50 50 47
– Late (months to years). Brachial plexus 62 61 60
• While acute radiation

pneumonitis responds to
corticosteroids, late
pneumonitis does not
respond.
• Other toxicities
encountered include,
transverse myelitis,
esophageal strictures or
perforation.

Radiation Pneumonitis
Latent phase: Loss of type 2 pneumocytes,
• Incidence of radiation
pneumonitis is related to:
Depletion of surfactant production and
– Dose. resultant protein translocation into the alveoli
– Fractionation.
– Volume of lung irradiated. Edema of interstitial spaces
– Pre-treatment pulmonary
function.
Thickening of alveolar septa
– Administration of
concurrent chemotherapy,
especially Bleomycin.
Acute clinical phase: Cough, dyspnea
• Asymptomatic radiological
findings may be seen in
50% patients. Loss of capillaries and collagen deposition
• Clinical radiation
pneumonitis may develop
in as many as 20% Chronic restrictive changes
patients.
Pathophysiology of Radiation Pneumonitis

Radiation Pneumonitis
• Typical manifestations include fever,

dyspnea, tachycardia and hypoxia.
• PFT reveals:
– Exercise induced oxygen desaturation
(early change).
– Decreased diffusion capacity.
• X ray findings:
– B/L airway disease.
– Vertical (non segmental).
– Confined to portals.
• CT findings:
– Homogeneous slight increase in
attenuation (2-4 mo)
– Patchy consolidation (1-12 mo)
– Non-uniform discrete consolidation (3
mo - 10 yrs)
• V/Q scans frequently reveal a
perfusion defect!

Radiation pneumonitis: Predictors
• Dosimetric predictors: Variable Cutoffs % toxicity

– Mean lung dose. ( ≥ Gr 2)
– Volume of lung group V 20 22 – 32% 7%

receiving ≥ 20 Gy (V20) 32 – 40% 13%
>40 % 36%
• Other predictors: Mean Lung < 20 Gy 8%
– Lower lobe treatment dose >20 Gy 24%
– Pretreatment functional
capacity
– Concurrent CCT
– Smoking (?)
– Peripheral location
– Increased serum TGF-β

Brachytherapy
• As far back as 1922, Yankauer placed capsules of

radium through a rigid bronchoscope into the
region of bronchogenic carcinoma.
• Brochoscopic afterloading flexible applicator based
technique first reported by Mendiondo et al.
• Role:
– As a palliative measure
• Indications:
– Patients with clinically significant endobronchial
component who are not suitable for other forms of
therapy.
– Life expectancy > 3 months.
– Ability to tolerate a bronchoscopy.
– Absence of bleeding diathesis.

Technique
• Uses Ir192 remote
afterloading HDR
brachytherapy.
• The total length of
endobronchial component
with 2 cm margins on
either side treated.
• Usual treatment length is
6-10 cm.
• Source is passed through a
6 F catheter placed
transnasally under
bronchscopic guidance.
• Dose prescribed is 8 Gy in
2# after XRT.
• Dose is prescribed at 1 cm
from the central axis of the
source.

Results
Author Schedule Symptom control
Dyspnea Cough Hemoptysis Duration
Bedweinek XRT 50 Gy  6 Gy x 3 71% 81% 81% 5 months
Speiser 10Gy x 3 ± XRT 60Gy
10Gy x 3 ± XRT 37.5Gy 86% 85% 99% NA
EBBT 7.5Gy x 3
Gollins 15 – 20 Gy x 1 60% 60% 88% NA
PGI results 8Gy x 2# + XRT 30Gy
5–7
10Gy x 1# + XRT 30Gy 91% 84% 94%
months
15Gy x 1#
• In another previous series the duration of symptom relief was

found to be 6 months when EBBT was added to XRT 30 Gy in
10# (Sharma et al).
• The most feared complication is massive hemoptysis which
may occur in as many as 10% in some series.

Chemotherapy
&
Targeted therapy
Chemotherapy
• Based upon the premise that 70% - 80%

patients will have micrometastasis during
presentation.
• Situations where CCT can be used:
 Neoadjuvant CCT as an induction regimen
 Adjuvant chemotherapy with or without
radiation*
 Palliative chemotherapy in systemic disease.
• No advantage of consolidation
chemotherapy has been established.

CCT regimens
• Standard chemotherapy Gemcitabine 22%

regimens:
– CAP regimen (q 3 weekly x 6 Paclitaxel 25%
cycles)
Vinorelbine 29%
• Cyclophosphamide
• Adriamycin
Irinotecan 30%
• Cisplatin
– CVP regimen Mitomycin C 25%
• 3 drug regimens have better
response rates but survival Vinbasltine 27%
benefit is absent.
Ifosfamide 23%
• In a study by Schiller et al using
4 different platinum based CCT Cisplatin 21%
regimens* failed to reveal any
benefit of a particular 0% 10% 20% 30% 40%
combination.

Induction CCT
• Induction CCT is a sometimes used in stage III A patients to
make them suitable for surgery  Downstaging is the intent
of treatment.
• Disadvantage:
– Delay in initiation of radiotherapy if patient fails to respond to
CCT
– Some patients otherwise suited for primary surgery may have
disease progression during CCT itself.
• Approach remains valid in a very small selected group of
highly motivated and affordable patients with good general
condition preferably in a trial setting!
Author Regimen N RR Survival Median

Survival
Roth et al CEP x 3  Sx 28 35% 56% (3yr) 64 mo
Sx alone 32 - 15% (3yr) 11 mo
Rosell et al IPM x 3  Sx 30 30% - 1 Mo
Sx alone 30 - - 8 mo
Adjuvant CCT
• Results:
– NSCLC-CG performed a metaanalysis examining
survival in 9387 patients (7151 deaths) in 52
randomized clinical trials.
• Cisplatin-based chemotherapy regimens appeared to
improve survival in patients undergoing resection by
5% but benefit was stastically insignificant.
• Survival benefit of 2-4% is expected
against an expected mortality of 1-2%
directly related to CCT toxicity.
• Relative chemoresistance of NSCLC makes
the approach even more questionable.

Results : Advanced cases
Author Regimen RR Median 1 yr
Survival OS
LeChevalier et al Cisplatin + Vinorelbine 30% 9.3 mo 35%
Cisplatin + Vindesine 19% 7.4 mo 27%
Vinorelbine 14% 7.2 mo 30%
Scagalotti et al Cisplatin + Gemcitabine 30% 9.8 mo 37%
Cisplatin + Paclitaxel 32% 9.9 mo 43%
Cisplatin + Vinorelbine 30% 9.5 mo 37%
Behra et al Cisplatin + Mitomycin + Ifosfamide 50% 5 mo 9
.8%
• In the study reported from PGI:

• 33% patients couldn't take more than 1 cycle due to toxicity,
lack of affordability or death.
• Survival was significantly correlated with performance status.
• Thus even in advanced disease RT probably a better option
specially in most patients in our setup.

Summary of CCT evidence
• Evidence for any beneficial effect of CCT exists for patients

with:
– WHO performance status 0 – 2
– Age < 70 yrs.
• Platinum based regimens should be used and single
agent CCT should be avoided (except in selected PS 2
patients)
• Adjuvant CCT after Surgery is not recommended without
further evidence of its efficacy.
• Median prolongation of survival is approx 3.4 months in
the palliative care setting but QOL is better than with BSC.
• Aggressive CCT regimens have failed to demonstrate a
survival advantage over conventional regimens despite the
cost and toxicity.

Targeted therapy
• EGFR Inhibitors
– Gefitinib (Iressa)
– Erlotinib (Tarceva)
• EGFR Monoclonal antibodies
– Cetuximab (Erbitux)
• VEGF Monoclonal antibodies
– Bevacizumab (Avastin)
• Many ongoing trials but what has emerged from already
concluded ones is:
 Iressa does not prolong survival & no benefit from adding to
chemo also (IDEAL phase II trials, INTACT & ISEL phase III
trials)
 Erbitux may not show any benefit in combination with chemo
 Avastin may show improved response in combination with
chemo but there is increased Grade III hemoptysis in
squamous cell carcinomas (10%).
 Median time to progression increased by a mere 3 months.

Therapeutic approach
Fit Surgery
Fitness
Stage I & II
for Sx
Unfit
RT (±
Inoperable
CCT)
Borderlin Induction
NSCLC Stage III No
e CCT
Fitness
for Sx
Operabl Surger
e y
Adjuvant RT ± CCT
 Palliative RT / CCT
 Supportive care
Stage IV  Hospice care
 Medication
 Brachytherapy
Conclusions
• Lung cancer remains a fatal disease in 70% - 80%

patients affected.
• Surgery remains the gold standard treatment in
patients with early resectable disease.
• Radiation has an important part to play in all
stages & for radical treatment as well as palliation.
• In India however majority of patients present with
advanced disease suited for palliation only.
• Alternate fractionation and chemoradiation are yet
to prove their mettle in our setup.
• Systemic therapy remains ineffective and costly
for this disease.
Prevention through education and legislation
remains the most cost effective way to
reduce incidence and mortality.

Wayne McLaren as the Marlboro man (1976) Dying from Lung Cancer (1992)
Seminar on NSCLC, Department of Radiotherapy, PGIMER.93

Moderat
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Non Small Cell Lung Cancer

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Non Small Cell Lung Cancer

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Non Small Cell Lung Cancer

Moderator : Dr. R. Kapoor

• Most common malignancy in males around

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

• Independent anatomical &

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Level 1: Highest Mediastinal nodes

Level 4: Lower paratracheal nodes

Level 10: Hilar nodes

Level 11: Interlobar nodes

Level 12, 13, 14: Lobar, segmental &

Level 7: Subcarinal nodes nodes

Level 8: Paraesophageal nodes

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Level 3A and 3P: Prevascular and

Level 6: Paraaortic nodes

Level 5: Subaortic nodes

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Bronchial surface epithelial type

Adenosquamous Bronchial gland type

Carcinomas with sarcomatous elements

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Squamous cell Carcinomas

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Incidence per 100,000

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

– Limitation of chest movement Carcinoid Syndrome

• Paraneoplastic syndromes: Acanthosis nigricans

– Cancer cachexia (MC) Hyperkeratosis

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

• Investigations to confirm the disease

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Most valuable invasive investigation as it allows:

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

IIIB T4 N0-N2 M0 10% 2.50%

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

• Tumor size cutoff of 3 cm.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

• Free resection margins proved

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Lobectomy /Lesser Pneumonectomy

FEV1 > 1.5 L FEV1 > 2 L

Operate •V/Q scan Operate

< 40% > 40%