non small cell lung cancer

Non Small Cell Lung Cancer

Moderator : Dr. R. Kapoor

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

IntroductionIntroduction

• 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.


AnatomyAnatomy


Bronchopulmonary segmentsBronchopulmonary 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 DrainageLymphatic Drainage

Level 1: Highest Mediastinal nodes

Level 2: Upper paratracheal nodes

Level 4: Lower paratracheal nodes

Level 7: Subcarinal nodes nodes

Level 8: Paraesophageal nodes

Level 9: Pulmonary ligament nodes

Level 10: Hilar nodes

Level 11: Interlobar nodes

Level 12, 13, 14: Lobar, segmental & subsegmental nodes


Lymphatic DrainageLymphatic Drainage

Level 6: Paraaortic nodes

Level 5: Subaortic nodes

Level 3A and 3P: Prevascular and retrotracheal nodes

Classification & Pathology


PathologyPathology

Primary Lung Cancer

Non Small cell type (70% - 80%) Small Cell type (20% – 30%)

Squamous cell (30 - 50%)

Adenocarcinoma (20 - 40%)

Large Cell (10 – 15%)

Adenosquamous

Carcinomas with sarcomatous elements

Neuroendocrine

Others

Bronchial surface epithelial type

Goblet cell type

Clara cell type

Type II alveolar cell type

Bronchial gland type


Squamous cell carcinomaSquamous 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.


AdenocarcinomaAdenocarcinoma

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 typesSpecial 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 FactorsRisk 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: AssociationSmoking: Association

• Incidence trends reveal a matching rise and fall with changes in smoking habits.

• Rising trend in women correlates with rising incidence of smoking in them

• Persistent smoking was associated with a 16-fold increase in cumulative lung cancer risk

• Risk is doubled if smoking commenced before age 15.

• Duration and intensity are both correlated the former in a exponential fashion.

• Cancer risk declines substantially after cessation.• Even passive smoking is associated with an

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.

``A cigarette is a euphemism for a cleverly crafted product that

delivers just the right amount of nicotine to keep its user addicted for life before killing the person.''

World Health Organization director-general Gro

Harlem Brundtland


Pathogenesis: Squamous typePathogenesis: Squamous type


Pathogenesis: AdenocarcinomaPathogenesis: Adenocarcinoma

Presentation


Incidence & PrevalenceIncidence & Prevalence

Incidence per 100,000

55.7

51.2

22

44.6

67.5

12.1

33.5

22

12.9

13.3

26.6

3.8

0 20 40 60 80

USA

UK

Sweden

Japan

China

India

Males Females

0

20

40

60

80

100

120

1974

1976

1978

1980

1982

1984

1986

1988

1990

1992

1994

1996

1998

2000

2002

Male Female


SymptomsSymptomsS

ympt

oms

Cough

Central growthHemoptysis

Dyspnea / Wheeze

Pneumonitis

Peripheral growth

Pain

Cough

Dyspnea

Lung abscess

Regional Spread

Hoarseness

Dysphagia

Diaphragmatic palsy

Horner’s Syndrome

SVC syndrome

Pancoast syndrome


SignsSigns

• Signs directly caused by tumor invasion or compression:– Limitation of chest movement– Rib tenderness– Vocal cord palsy– Horner’s syndrome– Engorged veins in the chest

wall and face• Signs due to metastasis

– Bony tenderness– Adrenal insufficiency– Organomegaly

• Paraneoplastic syndromes:– Cancer cachexia (MC)– Hypercalcemia– HPOA & clubbing

SIADH

Cushing’s Syndrome

Carcinoid Syndrome

Gynecomastia

Cerebellar degeneration

Eaton Lambert syndrome

Autonomic neuropathy

Optic neuritis

Pure red cell aplasia

DIC

Anemia, thrombocytopenia

Acanthosis nigricans

Hyperkeratosis

Hypertrichosis

VIP induced diarrhea

Hyperamylesmia


InvestigationsInvestigations

• 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 rayChest X ray


ImagingImaging

• 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.


BronchoscopyBronchoscopy

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


StagingStaging

• T1: – 3 cm or less,

completely covered by pleura, does not involve main bronchus


StagingStaging

• 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.


StagingStaging

• T3: – Chest wall– Diaphragm– Mediastinal pleura– Pericardium– Main bronchus <2cm to

carina– Complete atelectasis /

obstructive pneumonitis of entire lung


StagingStaging

• T4: – Carina– Vertebrae– Great Vessel– Esophagus– Heart– Separate tumour

nodule in same lobe– MALIGNANT pleural /

pericardial effusion


StagingStaging

• 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 2002Staging: AJCC 2002

Stage TNM

T N M

IA T1 N0 M0

IB T2 N0 M0

IIA T1 N1 M0

IIB T2 N1 M0

T3 N0 M0

IIIA T3 N1 M0

T1-T3 N2 M0

IIIB T4 N0-N2 M0

T1-T4 N3 M0

IV T1-T4 N0-N3 M1

5 yr overall survival

67%

55%

45%

22.50%

2.50%7.50%

55%

0%

10%

20%

30%

40%

50%

60%

70%

80%

IA IB IIA IIB IIIA IIIB IV


Staging ControversiesStaging 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 FactorsAdverse 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 & ScreeningPrevention & 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 : TypesSurgery : 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 dissectionLymph 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 ResectionComplete 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 algorithmSurgery : PFT based algorithm

Surgery Type

Lobectomy /Lesser Pneumonectomy

FEV1 > 1.5 LFEV1> 60%DLCO > 60%

FEV1 > 2 LFEV1> 60%DLCO > 60%

Operate Operate•V/Q scan•Calculated Post operative FEV1 & DLCO

< 40% > 40%

Exercise study

V02 max < 15 ml/kg/min V02 max > 15 ml/kg/min

Medically inoperable

Average risk


Criteria for inoperabilityCriteria 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.


ResultsResults

• T1 tumors: – Five-year overall

survival: 82%.– 10 year overall survival:

74%.

• T2 tumors:– Five-year overall

survival: 68%.– 10 year overall survival:

60%

• Morbidity:– 15% reduction in

spirometric values in lobectomy

– 35% - 45% reduction after pneumonectomy.

• Mortality:– 7% perioperative

mortality for pneumonectomy.

– 4% perioperative mortality for lobectomy


Patterns of failurePatterns 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 RadiotherapyRole 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 techniquesTreatment 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 radiotherapyCurative radiotherapy

• Indications for curative definitive radiotherapy:– Histologically proven

squamous cell carcinoma.– Medically inoperable

patients with localised tumors.

– Unimpaired functional status with or without symptoms (WHO < 2).

– Weight loss lesser than 6%.

– No evidence of distant metastasis.

• Contraindications for curative definitive radiotherapy are:– SVC syndrome.– Paralysis of recurrent

laryngeal nerve.– Paralysis of phrenic nerve.– Pleural or pericardial

effusions.– Extensive infection

including abscess formation

– Destructive involvement of chest wall.

– Superior sulcus tumors


TechniqueTechnique

• 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 SelectionField 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 techniquesAdvanced 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 exampleIMRT : Institutional example


IMRT : Institutional exampleIMRT : Institutional example

PTV

Esophagus

Spinal Cord


ResultsResults

• 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 lungProblems 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 IResults: Stage I

Authors Dose % T1 3 yr OS 3 yr CSSIntercurrent

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 stagePatterns 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?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 DiseaseRT: Advanced Disease

• Aim: – To achieve local

control due to high probability of death due to progression of systemic disease.

• Indications:– T3 disease– N1 or small N2 disease– No evidence of distant

metastasis– Weight loss < 12% of

body weight– < 50% of normal

working time spend in bed.

• Aim:– To achieve relief of

symptoms only when disease is too advanced for local control

• Indications:– T4 disease– Extensive N2 or N3

disease– Distant metastasis– Weight loss > 12% of

body weight– > 50% of normal

working time spend in bed.


TechniqueTechnique

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.


TechniqueTechnique

• 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?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 CourseRT results: Split Course

• Split course RT is criticized due to the radiobiological claim of tumor repopulation during the break.

• However in two randomized studies by Holsti et al (1980) and Lee et al (1976) no survival advantage of continuous course RT could be demonstrated.

• In another series by Perez et al (RTOG 73-01), the survival for patients receiving split course was comparable after 4 years to those receiving a continuous regimen (stage I/II).

• However they also reported a lower in field control rate for split course regimen. 0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

1 yr 2 yr 3 yr 4 yr

Continous Split Course


Special SituationsSpecial Situations

SVC Syndrome• Patient should be started on

decongestive measures prior to starting radiotherapy.– I/V steroids– Moist Oxygen– Bronchodilators

• RT induced edema can exacerbate symptoms in the first few days

• 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– 8 Gy in SF

• Regimen selected depends on patient age and GC.

Symptomatic Relief from SVC Syndrome after RT

50%

15%

15%

20%

Excellent Good

Minimal No response


Superior Sulcus TumorsSuperior 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: ResultsSST: 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 SSTInoperable SST

• Surgery is contraindicated in patients with:– Horner’s Syndrome– Rib destruction– Brachial plexus

involvement.– Major vessel

involvement.

• Treatment goal is palliation of symptoms.

• RT/CCT are the main therapeutic modalities.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Pain relief Horner'sSyndrome

3 yr Survival


Dose IntensificationDose 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


HyperfractionationHyperfractionation

• 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 & CHARTWELCHART & 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


ChemoradiationChemoradiation

• 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 : ResultsSequential CCT +RT : Results

Author Regimen N Median Survival

3 yr OS

Dilman et al (CALGB)

RT (60) 77 9.7 mo 11%

PV RT (60) 79 13.8 mo 23%

Sause et al (RTOG 88-08)

RT (60) 149 11.4 mo 6%

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 : ResultsConcomitant 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-Koning et al

(EORTC)

RT (55) 108 - 13%

P + RT (55) 98 - 19%

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%

• 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).

**Carboplatin and etoposide


RecommendationsRecommendations

1. Useful in patients with good general condition and performance status only.

2. Single agent CCT is no better than radiation alone when used sequentially.

3. Should be using a platinum based regimen as other regimens have not resulted in an improved survival (Pujol et al).

4. Concurrent CCT is better than sequential but also leads to a greater toxicity (RTOG 9401 results).

5. Higher levels of hematotoxicity should be anticipated before hand.

6. Should be reserved for the trial setting because of the toxicity may not be routinely manageable.


PGI resultsPGI 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 RadiotherapyPostoperative 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.


ResultsResults

• 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 radiotherapyPreoperative 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: ToxicityRadiotherapy: Toxicity

• The most common and significant radiation toxicity is radiation pneumonitis.

• Occurs in two forms:– Acute (1-6 months).– Late (months to years).

• While acute radiation pneumonitis responds to corticosteroids, late pneumonitis does not respond.

• Other toxicities encountered include, transverse myelitis, esophageal strictures or perforation.

TD 5/5 Volumes & Tolerance (Gy)

Organ 1/3 2/3 3/3

Lung 45 30 17.5

Heart 60 45 40

Esophagus 60 58 55

Spinal cord 50 50 47

Brachial plexus 62 61 60


Radiation PneumonitisRadiation Pneumonitis

• Incidence of radiation pneumonitis is related to:– Dose.– Fractionation.– Volume of lung irradiated.– Pre-treatment pulmonary

function.– Administration of

concurrent chemotherapy, especially Bleomycin.

• Asymptomatic radiological findings may be seen in 50% patients.

• Clinical radiation pneumonitis may develop in as many as 20% patients.

Latent phase: Loss of type 2 pneumocytes,

Depletion of surfactant production and resultant protein translocation into the alveoli

Edema of interstitial spaces

Thickening of alveolar septa

Acute clinical phase: Cough, dyspnea

Loss of capillaries and collagen deposition

Chronic restrictive changes

Pathophysiology of Radiation Pneumonitis


Radiation PneumonitisRadiation 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: PredictorsRadiation pneumonitis: Predictors

• Dosimetric predictors: – Mean lung dose.– Volume of lung group

receiving ≥ 20 Gy (V20)

• Other predictors:– Lower lobe treatment– Pretreatment functional

capacity– Concurrent CCT– Smoking (?)– Peripheral location– Increased serum TGF-β

Variable Cutoffs % toxicity ( ≥ Gr 2)

V 20 22 – 32% 7%

32 – 40% 13%

>40 % 36%

Mean Lung dose

< 20 Gy 8%

>20 Gy 24%


BrachytherapyBrachytherapy

• 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.


TechniqueTechnique

• 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.


ResultsResults

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 60Gy10Gy x 3 ± XRT 37.5GyEBBT 7.5Gy x 3

86% 85% 99% NA

Gollins 15 – 20 Gy x 1 60% 60% 88% NA

PGI results 8Gy x 2# + XRT 30Gy10Gy x 1# + XRT 30Gy15Gy x 1#

91% 84% 94%5 – 7

months

• 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


ChemotherapyChemotherapy

• Based upon the premise that 70% - 80% patients will have micrometastasis during presentation.

• Situations where CCT can be used:Neoadjuvant CCT as an induction regimenAdjuvant chemotherapy with or without

radiation*Palliative chemotherapy in systemic disease.

• No advantage of consolidation chemotherapy has been established.


CCT regimensCCT regimens

• Standard chemotherapy regimens:– CAP regimen (q 3 weekly x 6

cycles)• Cyclophosphamide• Adriamycin• Cisplatin

– CVP regimen

• 3 drug regimens have better response rates but survival benefit is absent.

• In a study by Schiller et al using 4 different platinum based CCT regimens* failed to reveal any benefit of a particular combination.

21%

23%

27%

25%

30%

29%

25%

22%

0% 10% 20% 30% 40%

Cisplatin

Ifosfamide

Vinbasltine

Mitomycin C

Irinotecan

Vinorelbine

Paclitaxel

Gemcitabine


Induction CCTInduction 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 MedianSurvival

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% - 26 Mo

Sx alone 30 - - 8 mo


Adjuvant CCT 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 casesResults : Advanced cases

Author Regimen RR Median Survival

1 yr 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 evidenceSummary of CCT evidence

1. Evidence for any beneficial effect of CCT exists for patients with:– WHO performance status 0 – 2– Age < 70 yrs.

2. Platinum based regimens should be used and single agent CCT should be avoided (except in selected PS 2 patients)

3. Adjuvant CCT after Surgery is not recommended without further evidence of its efficacy.

4. Median prolongation of survival is approx 3.4 months in the palliative care setting but QOL is better than with BSC.

5. Aggressive CCT regimens have failed to demonstrate a survival advantage over conventional regimens despite the cost and toxicity.


Targeted therapyTargeted 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 chemoAvastin 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 approachTherapeutic approach

NSCLC

Stage I & II

Fit

Unfit

Fitness for Sx

Surgery

RT (± CCT)

Stage IV

Palliative RT / CCT Supportive care Hospice care Medication Brachytherapy

Stage III

Operable

Inoperable

Borderline

Surgery

Adjuvant RT ± CCT

Induction CCT

Fitness for Sx

No


ConclusionsConclusions

• 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.


93

Wayne McLaren as the Marlboro man (1976) Dying from Lung Cancer (1992)

Thank You

non small cell lung cancer

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