Non Small Cell Lung Cancer

Non Small Cell Lung Cancer

LUNG CANCER- TREATMENT RECENT ADVANCES & RESULTS

Presenter- Dr.Jyotindra singhNIMS,HYDERABAD

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.

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

Classification & Pathology

Classification & Pathology

PathologyPathology

Squamous cell carcinomaSquamous cell carcinoma

Incidence of SCC appears to be decreasing relative to adenocarcinoma.

• Arise centrally –(two third) within the main, lobar, segmental or subsegmental bronchi.

• Grow slow,metastasize late

• Extends both intrabronchially & peribrionchially.

• 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.

• Peripherally located-undergo central necrosis with resultant cavitation

SCC

Adeno Ca.

Squamous cell carcinomaSquamous cell carcinoma

• Better prognosis than adenocarcinoma

• The more necrosis – the worse the prognosis

• Well differentiated SCC – more locoregional spread

• Poorly differentiated SCC – early metastases to distant sites

• Alveolar filling of peripheral SCC – more favorable prognosis

CAVITATTION DUE TO TUMOUR NECROSIS

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.

AdenocarcinomaAdenocarcinoma On routine medical examination, the chest film of a

64-year-old man shows bilateral primary lung tumours in the upper lobes; the lesion on the left side is partly obscured by the clavicle. (b) CT scan clearly defines the irregularly shaped primary lesions (arrows). Synchronous primary lung cancers occur in about 3-5% of patients and can be of different histologic subgroups.

PROGNOSTIC FEATURESPROGNOSTIC FEATURES• Scar carcinoma- poor

• Central fibrosis<5mm- excellent,>15mm – worst

• Ground glass opacity <3 mm on HRCT –Better prognosis.

• Incidence of lymph node involvement is less or even absent when greater percentage of ground glass appearance.

• Central tumours- higher incidence of LN metastasis.

• BAC (variant)- higher incidence of LN involvement .

• Neuroendocrine differentiation,WDFA –poor prognosis.

,

EGFR

KRAS

BRAF

HER2PIK3CA

ALK

No known genotype

ROS1RET MET

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

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

SymptomsSymptomsS

ympt

oms

Cough

Central growth

Hemoptysis

Dyspnea / Wheeze

Pneumonitis

Peripheral growth

Pain

Cough

Dyspnea

Lung abscess

Regional Spread

Hoarseness

Dysphagia

Diaphragmatic palsy

Horner’s SyndromeSVC

syndromePancoast 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

ImagingImaging

• Plain X rays– A tumor visible in a chest X ray has usually completed 75% of it’s

natural history.– Guides local radiotherapy

• 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.

• PET CT has a greater degree of sensitivity for detection of nodal disease that would be missed by size based criteria alone.

Mediastinal NodesMediastinal NodesEBUS CT PET

Sensitivity 92% 76% 80%

Specificity 100% 55% 70%

Accuracy 98% 61% 73%

\.

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 & PrognosisStaging & 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 MIA 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

Chart illustrates the descriptors from the 7th edition of the TNM staging system for lung cancer.

2010;30:1163-1181

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.

• 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

Small cell lung carcinomaSmall cell lung carcinoma

• 15 – 25 % of all lung cancers• Almost exclusively in smokers• Distinguished from NSCLC by:

– Rapid doubling time– High growth fraction– Early development of wide-spread

metastasis • Typically arise centrally• Most common presentation is a large

hilar mass with bulky mediastinal LAN

• Commonly spread to liver, adrenals, bone and brain.

• produces paraneoplastic Syndrome.

• Tumour markers-3 main groups: Neural, Epithelial, Neuroendocrine.

VALG STAGING SYSTEM VALG STAGING SYSTEM• Very-limited disease: confined to one

hemithorax without mediastinal lymph node involvement.

• Limited disease: confined to one hemithorax including the contralateral lymph nodes (all within radiation field).

• Extensive disease: beyond these bounderies.

• Very-limited disease ~ 5 years• Limited disease 18-24 months• Extensive disease 10 months

• SCLC without treatment < 3 months

PROGNOSTIC FACTORSPROGNOSTIC FACTORS

• The host factors of poor performance status and weight loss

• Stage (limited versus extensive).

• In extensive disease, the number of organ sites involved is inversely related to prognosis

• Metastatic involvement of the central nervous system, the marrow, or the liver is unfavorable compared to other sites

• In most trials, women fare better than men, although the reasons for this are not known.

• The presence of paraneoplastic syndromes is generally unfavorable

LIMITED STAGE LIMITED STAGE

• Combination of chemo & radiation

• combination chemotherapy is the backbone of treatment

• thoracic radiotherapy significantly improves long term survival

• Early thoracic radiotherapy gives better results than late radiotherapy.

• Cisplatin and etoposide are most easily combined within concurrent chemoradiation protocols (Turrisi et al )

• BID radiotherapy gives better local control and better long term survival than QD (5y survival %: 26% Turrisi et al, NEJM 99 )

• PCI significantly improves survival by 4-5 % at 5 years when given to complete responders (Auperin et al )

SCLC LD Standard of treatmentSCLC LD Standard of treatment

Cisplatin 80 mg/m2 d1

Etoposide 120 mg/m2 d1-3

Q3wk x 4

Thoracic Radiotherapy 45 Gy 1.5 Gy/fraction bid 3 wk

Turrisi et al. NEJM 1999

EXTENSIVE STAGE DISEASEEXTENSIVE STAGE DISEASE• Primary treatment is chemo

• Cisplatin or Carboplatin plus Etoposide – Median survival approx. 11

months– 5 year survival approx 0%

• Second line therapy> 95 % relapse after first-line treatment

• Topotecan for chemo sensitive relapse dosease

• Role of PCI

• No improvement achieved by– Novel agents (taxanes, topo 1

inhibitors)– Biologicals

Topotecan(n=71)

BSC(n=70)

HR (95%CI)P-value

MS (weeks)

26 14 0.64P = 0.0104

6 mo survival

49% 26%

SurgerySurgery

Surgical Aspects in Lung Cancer ManagementSurgical Aspects in Lung Cancer Management

• How fit is the patient ?• What is the stage, histology,

and exact size and location ?

• Is the patient for – Diagnosis– Treatment– Palliation

• Diagnostic– Bronchoscopy– VATS– Mediasteinoscopy– Mediasteinotomy

• Treatment– Wedge– Lobectomy– Combined wedge and

lobectomy– Pneumonectomy

• Palliation– Effusions

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

NSCLC: Stage at DiagnosisNSCLC: Stage at Diagnosis

• Stage I and II – Surgery as primary treatment

• Stage III – Multimodality Therapy

• III A – Neoadjuvant therapy

(chemo/radiation) followed by

surgery & additional therapy

III B – Combination chemotherapy

& radiation therapy.

• Stage IV – Palliative chemotherapy

and/or radiation ,best supportive

care

Stage IV 40%

Stage I 10%

Stage II 20%

Stage IIIA 15%Stage IIIB

15%

Ettinger et al. Oncology. 1996;10:81-111.

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.

THORACOTOMYTHORACOTOMY

Posterolateral

Anterolateral

Lateral

Mini

Muscle sparing

SEGMNENTECTOMY WEDGE RESECTIONSEGMNENTECTOMY WEDGE RESECTION

• Small peripheral tumour confined to an anatomic segment.

• Patient has limited pulmonary reserve.

• Low grade tumour under investigation.

• Lingulectomy( encompassing 2 segments)- peripheral NSCLC.

• LCSG report Ginsberg- limited resection for T1N0 NSCLC- local recurrence 3 fold higher than for lobectomy although ultimate survival not significantly different,

• Non anatomic and definitive therapy only in poor risk patients.

• CRITERIA FOR WEDGE RESECTION

• A tumor < 3cm in diameter• Location in outer third of lung• Absence of endobronchial extension.• Clear margins by frozen section• negative mediatinal & hilar node

sampling.

• CALBG ( cancer & leukemia Group B ) - Trial of lobectomy vs sublobar resection.

• ACOSOG – Trial sublobar resection vs sublobar resection + implanted radiation seeds.

Segmentectomy vs wedge rxnSegmentectomy vs wedge rxn

• Segmentectomy– Better deep margin (El Sharif et al Ann Surg Onc 2007)

– Better nodal evaluation/clearance• Wedge resection

– Adequate for peripheral (subpleural), small (1 cm) lesions when margin is wide (diameter of lesion or more)

– If lesion straddles segmental boundary (i.e. between lingula and upper division)

LOBECTOMY BILOBECTOMYLOBECTOMY BILOBECTOMY• Resection of a lung cancer confined to

parenchyma of a single lobe.

• Removal of tumour + peripheral (pleural ) & central lymphatic drainage pathways

• Leaves sufficient lung volume to fill the pleural void.

• Ginsberg reported operative mortality – 2% vs 4 % for pneumonectomy.

• Involves resection of right upper and middle lobe or of the right middle & lower lobe-

• when a tumour located in anterior segement of RUL

• Tumour in RML has spread across the minor fissure or approximates an incomplete fissure.

• When tumour in RML is central-proximity of the origins of superior segmental and middle lobe bronchi

• Interlobar vascular vascular or nodal involvement.

VATS LobectomyVATS Lobectomy

Absolute containdiactions• Inability to achieve complete resection

–T3 or T4 tumors–N2 or N3 disease

• Inability to obtain single lung ventilation• Large Tumor > 5 cm (too large to remove

through utility incision)

Relative• Conditions that compromise the safety of

dissection-- Pre-op chemotherapy / radiation therapy or both

-- Presence of hilar lympnadenopathy complicating dissection-- Presence of extensive adhesions

• Invasion of extra-pulmonary structure

• 1281 Propensity matched patients (945 VATS, 857 thoracotomy)

• Fewer overall complications (35.7% vs. 26.2% p <.0001)– Decreased arrhythmias– Fewer pulmonary complications– Fewer Blood transfusions

• Shorter Hospital Stay (4 vs. 5 days)• Equal operative mortality (1%)

Fewer complications Hoksch1

Less pain Walker2

Better quality of life Sugiura3

Better PFTs Nakata4

Less pneumonia Whitson5

Earlier recovery Demmy6

Easier for octogenarians McVay7

SLEEVE LOBECTOMYSLEEVE LOBECTOMY

• Resection of lobe along with a circumferential segment of mainstem bronchus.

• Indicated for endobronchial tumours at the origins of right or upper lobe bronchi.

• Tumour should be limited to the lung.

• Pts. With negative mediastinal node has the best survival.

• Anastomotic complications Granulations Stenosis Bronchovascular fistula

PneumonectomyPneumonectomy

• The indications are central tumors that involve the main bronchus

• Large parenchymal cancers that violate the fissures or invade the interlobar vessels, or hilar lymph node involvement.

• Pneumonectomy in the latter situation should be reserved for cases in which higher stations are benign and a complete resection is possible.

• The operative mortality for pneumonectomy is about twice that of lobectomy.

• Patients with N2 disease or centrally locally invasive tumours are treated by induction therapy- due to extent of their disease they need pneumonectomy

Extended Pneumonectomy

• Intrapericardial pneumonectomy

• Supra aortic pneumonectomy

• Carinal pneumonectomy

CHEST WALL INFILTRATIONCHEST WALL INFILTRATION

• Tumors invading the chest wall are often resectable.

• The involved ribs should be transected several centimeters beyond the margin of gross involvement.

• In most cases, one rib and intercostal tissue above and below the tumor should also be included in the resection.

• For posterior defects, support by the remaining chest wall muscles and scapula is usually sufficient.

• Anterior and lateral defects more often require reconstruction.

• For isolated chest wall invasion with N0 or N1 positive nodes, there is no known role for neoadjuvant therapy.

• There is controversy regarding the necessity of chest wall resection when invasion is confined to the parietal pleura.

DIAPHRAGMDIAPHRAGM

• When invasion occurs, that portion of the diaphragm should be resected with a wide margin of normal tissue without regard to the extent of the defect.

• If the defect is small and can be closed primarily without tension- Prosthetic material/muscle flap

• When a large area of diaphragm has been resected or when the phrenic nerve has been resected- diaphragmatic reconstruction.

• When the defect is peripheral, it may be possible to reinsert the remaining cut edge at a higher level on the chest wall

PERICARDIUMPERICARDIUM• Total resection of the pericardium on the

left can be performed without reconstruction.

• Partial defects should be closed to prevent herniation and strangulation of the left ventricle.

• On the right side, all pericardial defects, regardless of size, require repair.

• Large defects can be closed with the pericardial fat pad, a pleural flap, or nonautologous material such as bovine pericardium or polytetrafluoroethylene (PTFE).

• A small opening be left in the repair or that the prosthetic material be fenestrated to prevent cardiac tamponade.

VERTEBRAVERTEBRA

• Vertebral body invasion is considered T4 disease and thus unresectable.

• DeMeester and colleagues described a technique of partial vertebral resection for tumors fixed to the paravertebral fascia.

• They use a through the transverse process, costotransverse foramen, and superficial vertebral body

. En bloc pulmonary resection and complete vertebrectomy with reconstruction by a combined anterior and posterior approach.

Used when - tumor extent is completely delineated, node-negative, totally resectable, and, after careful evaluation with MRI, does not involve the spinal canal.

Pancoast tumorPancoast tumor

• “Pancoast Tumor” is a neoplasm located at the apical pleuropulmonary groove adjacent to the subclavian vessels.

• Symptoms arise as a result of neoplastic involvement of the brachial plexus, nerve roots, sympathetic chain, ribs, and chest wall.

• Ptosis of the left eyelid, miosis of the pupil and decreased sweating of the left face, arm and upper chest (Horner's syndrome)

• chest film- large tumour of the right upper lobe that has destroyed the adjacent rib.

• CT scan reveals rib and soft tissue involvement as well as destruction of an adjacent vertebral body.

• Biopsy showed a squamous cell carcinoma.

Many centres are now reportingmore adenocarcinomasthan squamous cell type.

Preliminary Supraclavicular Exploration

Preliminary Supraclavicular Exploration

• Dissection of:– Supraclavicular nodes– S.C. artery– Brachial plexus– Scalene muscles– Phrenic nerve

• Adverse prognostic factors:

– Horner’s syndrome

– N2, N3 disease

– Incomplete resection• 9% 5yr survival

Posterolateral (Shaw - Paulson)

Anterior cervicothoracic (Dartevelle)

Hemi-clamshell (Burt)

Anteroposterior “hook” (Niwa)

VATS - Posterior

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)

Technique of Mediastinal Lymph Node Dissection

Technique of Mediastinal Lymph Node Dissection

• Right Paratracheal – clear all tissue from SVC to trachea and from upper lobe bronchus to the subclavian artery

• Left Aorto-Pulmonary Window –clear all tissue from phrenic nerve to the descending aorta and from the left upper lobe bronchus to the subclavian artery

• Subcarinal- clear out all tissue bordered by the right and left bronchi and pericardium

Video Assisted Mediastinoscopic Lymphadenectomy (VAMLA)

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

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.

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%– 5 yr survival in clinical N2 negative nodes: 27%– 5 yr survival in clinical N2 positive nodes : 8%– 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.

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.– Associated comorbidities and poor lung function make

patients not suitable for surgery.– Advanced age and poor socioeconomic status make RT an

attractive treatment option.

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.

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 – Two techniques of respiratory gating are:

• Breathhold techniques:– Active : Using valves and spirometers– Passive: Voluntary breath holding

• Synchronized gating technique : Uses free breathing with synchronized beam delivery.

IMRTIMRT

Role of Postoperative RadiotherapyRole of 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 .

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.

Intraoperative BrachytherapyIntraoperative Brachytherapy

● Mostly used for Stage IIIA disease- close or positive

margins

● Improved local control

Cedars Brachytherapy

Cedars Brachytherapy

• 3 radiation catheters• Minimally invasive

surgery• Radiation beads are

placed down the catheters

• Then the beads are removed

• Very targeted – lung motion is not an issue

Catheters for radiation

beads

Chemotherapy &

Targeted therapy

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

First-line Therapy: 2013First-line Therapy: 2013

Column ACisplatin

Carboplatin

Column BVinorelbine

GemcitabinePaclitaxelDocetaxel

PemetrexedNab-paclitaxel

Irinotecan

Column CBevacizumabCetuximab?

Option 1: choose 1 from column A and 1 from column B Option 2: choose 2 from column B

Option 3: option 1 + column C (for certain patients)Option 4: choose 1 from column D (for selected patients)

Column DErlotinib

Crizotinib

National Comprehensive Cancer Network clinical practice guidelines in oncology: Non-small-cell lung cancer (v2.2013). www.nccn.org

y Advanced Non-Small-Cell Lung Cancer: 2013 GUIDELINES

Contenders for Second Line and BeyondContenders for Second Line and Beyond

• Non-small cell lung cancer–pemetrexed–gefitinib

• Small cell lung cancer– topotecan

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.

DNA

Membrane

Extracellular

Intracellular

R

K

R

K EGFR-TKIEGFR-TKI

SignallingProliferation Cell survival

(anti-apoptosis)

Growth factors

Chemotherapy/radiotherapy sensitivity

Angiogenesis

Metastasis

ûû

ûR, epidermal growth factor receptor

EGF/TGFα

Gefitinib: Mechanism of Action

• • Relatively new treatment concept• • Established in early 1990s at

Karolinska Institute, • Stockholm, Sweden • • Few fractions/high doses/steep

gradients• • Goal is tumor ablation

• indicated• – Medical inoperability• • Improved therapeutic ratio over

fractionated RT courses

Stereotactic Radiation for Lung Cancer (SBRT)

Stereotactic Body Radiotherapy VS Standard radiotheraypy

Standard radiotherapy – 6 weeks

5 year survival rates 10 – 30%

SBRT – 1 to 5 days

Local control rates 90%

3 year survival rates 56 – 60%

RTOG 0236

Results- Tumor Response After RFAResults- Tumor Response After RFA

• RFA is the use of high-frequency electrical current to heat a specific volume of tissue to temperatures high enough to cause destruction of undesired malignant cells.

•• Lifting of the deflated lower lobe off of the diaphragm and sometimes with takedown of the inferior pulmonary ligament in cases where the tumor is located in the lower lobe, is beneficial during ablation to protect the diaphram.

1

3 months post-RFA

CALGB 14053CALGB 14053

• Randomized trial of “sublobar resection” vs. Lobectomy

• Clinical stage IA(T1a) with PFTs adequate for lobectomy

• Lobectomy – VATS or Thoracotomy

• Sublobar Resection– Wedge resection or segmentectomy– VATS or Thoracotomy

Lung Cancer Surgery: futureLung Cancer Surgery: future

Wu C-Y, et. al. Ann. Thorac. Surg. 2013 Feb;95(2):405–11.

Gonzalez-Rivas D, et al. Multimedia Manual of Cardiothoracic Surgery. 2012 Mar

ConclusionsConclusions• Minimally Invasive Lobectomy is the new

standard for early stage lung cancer surgery

– Equivalent oncologic results– Decreased morbidity– Faster recovery– Improved completion of adjuvant therapy

• Thoracoscopic (VATS) Lobectomy is well established

• The roles of sublobar resection and Robotic surgery require further investigation

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator :

Dr. R. Kapoor

81

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

Death is a natural eventDeath is a natural event

THANK YOU

Standard of Care For Peripheral NodulesStandard of Care For Peripheral Nodules

1940’s Pneumonectomy

1960’s Lobectomy

1990’s ?Segmentectomy/Wedge (and adjuvant local/systemic Rx)

Surgical Resection of the Lung

Randomized Trial of Lobectomy Versus Limited Resection for

T1 N0 Non-Small Cell Lung Cancer(125 Lobectomy , 122 Limited Resection)

Randomized Trial of Lobectomy Versus Limited Resection for

T1 N0 Non-Small Cell Lung Cancer(125 Lobectomy , 122 Limited Resection)

RJ Ginsberg, LV Rubinstein and Lung Cancer Study Group

Ann Thorac Surg 1995;60:615-23

Lobectomy vs Limited Resection Time to death (from any cause) by treatment

Lobectomy vs Limited Resection Time to death (from any cause) by treatment

020406080

100120

% S

urviv

al Lobectomy

Limited Resection

logrank p=0.088 (one-tailed)

Ginsberg and RubinsteinAnn Thorac Surg

Wedge Resection Versus Lobectomy for Stage I (T1 N0 M0) Non-Small Lung Cancer

Wedge Resection Versus Lobectomy for Stage I (T1 N0 M0) Non-Small Lung Cancer

Landreneau, et.al.,

J Thorac Cardiovasc Surg 1997;113:691-700

Wedge vs Lobectomy for Stage I NSCLC

Wedge vs Lobectomy for Stage I NSCLC

0

20

40

60

80

100

120

0 10 20 30 40 50 60

% S

urvi

val

Wedge

Lobectomy

p=0.889

Landreneau, et.al.,J Thorac Cardiovasc Surg 1997;113:691-700

Wedge vs Lobectomy for Stage I NSCLC

Wedge vs Lobectomy for Stage I NSCLC

Open WR

VATS WR

Vs. Lobe P<

Op Mortality (%) 0 0 Vs. 3.3 0.20*

Postop Stay (days)

7.7 6.5 Vs. 10.1 0.0002*

Local Recur (%) 17 15 Vs. 5 0.08*

Local/Systemic Recurrence (%)

24 23 vs. 17 0.43*

*- all WR (n=95) vs. Lobe (n=124) Statistical Methods: Life Table Analyses Obtained by Log Rank and Wilcoxson Tests Landreneau, et.al.,

J Thorac Cardiovasc Surg 1997;113:691-700

Comparison Between Sublobar Resection and 125Iodine Brachytherapy After Sublobar Resection in High-Risk Patients with Stage I Non–Small-Cell

Lung Cancer      

     R.  Santos, A. Colonias, D. Parda, M. Trombetta, RH Maley, R. Macherey, S. Bartley, T. Santucci, RJ Keenan,

RJ Landreneau

 Surgery 2003, Oct;134(4): 691-7

Sublobar Resection

(n=102)

Sublobar Resection

With Brachy (n=96)

Local Recurrence 19 (18.6%) 1 (1%) p=.0001

Hospital Mortality 0 (0%) 3 (3%) p=ns

Hospital Stay 7 days 8 days p=ns

Survival %1, 2, 3 and 4 year 93, 73, 68, 60% 96, 82, 70, 67%

p=ns

Systemic Recurrence

29 (28.4) 22 (23%) p=ns

Pre-op FEV 1%predicted

65% 53% p=ns

ResultsResults

The FEV 1 did not change postoperatively in the sublobar resection with brachytherapy group in the interval of follow-up

Lobectomy vs Sublobar Resection

Lobectomy vs Sublobar Resection

“Effect of Tumor Size on Prognosis in Patients with Non-Small Cell Lung Cancer: The Role of

Segmentectomy as a Type of Lesser Resection”

Okada M, Nishio W, Sakamoto T, Uchino K, Yuki T,Nakagawa A, Tsubota N.

“J Thorac Cardiovasc Surg. 2005 Jan;129(1):87-93”

An evaluation of surgical resection in 1272 NSCLC patients

TUMOR SIZESegmentalResection Lobectomy

WedgeResection

20 mm or less 96.7 92.4 85.7

20-30 mm 84.6 87.4 39.4

More than 30 mm

62.9 81.3 0

Lobectomy vs Sublobar Resection

5 Year Cancer Specific Survival “Stage I”

“Okada, M, et al J Thorac Cardiovasc Surg. 2005 Jan;129(1):87-93”