Dr. P.K. Das Dr. P.K. Das MD, DM (Medical Oncology, AIIMS)MD, DM (Medical Oncology, AIIMS)

Senior Consultant Senior Consultant

Indraprastha Apollo HospitalIndraprastha Apollo Hospital

New DelhiNew Delhi

drpratapdas@gmail.comdrpratapdas@gmail.com

Web site- www.drpkdas.comWeb site- www.drpkdas.com

RECENT ADVANCES IN MANAGEMENT OF LUNG CANCER

Lung Cancer

• Epidemiology

• Etiology/Risk factors

• Diagnosis

• Histology

• Staging

• Various Treatment Options

• Complications

Over View

Worldwide incidence for lung cancer

Lung cancer is the most common cancer in the world

Lung Cancer Incidence

World >1.3 million

Continent % of World

Asia 49

Europe 28

North America 17

Central/South America

4

Africa 1

• Lung cancer is the most common cause of cancer deaths in the world

Kamangar et al. J Clin Oncol. 2006;24:2137-2150.

Lung Cancer Incidence – Geographical Variation

Kamangar et al. J Clin Oncol. 2006;24:2137-2150.

Districtwise Minimum Age Adjusted Incidence Rate Per 100,000 LUNG - Males

© Copyright National Cancer Registry Programme 2001-2004

Districtwise Minimum Age Adjusted Incidence Rate Per 100,000 LUNG -Females

© Copyright National Cancer Registry Programme 2001-2004

Etiology• Smoking (cigarette smoke has 300 chemicals, 40 of which

are carcinogenic) – 90 % patients are smokers

• Passive smoking/environmental tobacco smoke (ETS)/ second-hand tobacco smoke

• Asbestos

• Radiation

• Radon

• Air pollution

• Lung injury/disease

• Genetic factors ( EG F R, ras, p 5 3 )

Smoking

• Most lung cancers are caused by carcinogens and tumor promoters ingested via cigarette smoking

• Smoking — active ↑ risk about 13 fold ETS ↑ risk about 1.5 fold• Cessation of smoking ↓ chance of developing lung cancer but

may never return to nonsmoker level• Cigarette pack years – 2 packs/day for 2 0 years, ↑ 6 0 -7 0

fold risk • Efforts to get people to stop smoking are mandatory• Methods available for smoking cessation:

These methods are successful in only 2 0%-25% of smokers at one year (Preventing people from starting to smoke may be more effective)

B e h a v ior t h era p y

Nicotine replacement ( g um, patc h, sublingual spray & inhaler)

Lung Cancer Histology

Squamous-cell30%

Adenocarcinoma40%

Large-cell10%

Small-cell20%

Squamous cell & SCLC are decreasing in incidence

Diagnosis

•Patient History

•Physical Examination

•Diagnostic Studies

Diagnosis of Lung Cancer

•History and Physical Examination

– Medical History

– Risk factor assessment

– Checking of airways, lymph nodes, lung sounds etc

•Diagnostic tests

– Routine lab tests like Complete Blood Counts, chest X-rays, Liver function tests

– Non invasive tests – sputum cytology and imaging tests (CT, MRI, PET, Bone Scan)

– Invasive tests – Bronchoscopy, Transbronchial FNA, Transthoracic Percutaneous FNA, Mediastinoscopy, Mediastinotomy, etc

Clinical Manifestations

A cough that does not go away Chest pain, often made worse by deep breathing Shoulder pain with numbness in some fingers; with

or without droopy eyelid (HORNER’S SYNDROME) Hoarseness Weight loss and loss of appetite Bloody or rust-colored sputum Shortness of breath Fever without a known reason Recurring infections such as bronchitis and

pneumonia New onset of wheezing Headaches; change in vision or speech Seizures

Diagnostic Studies

– Imaging:

Used to visualize the interior of the body. Examples of

such studies include X-rays, Ultrasound, Computerized

Tomography (CT) scans, positron emission tomography

(PET), and magnetic resonance imaging (MRI)

– Endoscopy:

Involves use of a light on a flexible fiberoptic viewing

device (endoscope) to examine lining of the passages

Lung cancer presentation

The chest x-ray shows a shadow in the left lung, which was later diagnosed as lung cancer.

A CT scan of the lung shows a mass lesion in the right lung. The mass turned out to be lung cancer on examination of the needle biopsy sample.

PET (Positron emission tomography)

Computerized image of chemical changes eg sugar metabolism that take place in tumor tissue

Patient injected with radioactive sugar (FDG PET) and then scanned

Uptake will happen in active tumor : distinguish normal from abnormal tissue

PET Image

Histologic Examination

Tissue Acquisition Bronchoscopy Biopsy Core needle Fine needle Brush cytology Incisional Excisional Other procedures

MicroscopyGrading

G1 G2 G3, G4

Tissue Acquisition

Is done through biopsy – a procedure through which tissue or fluid is removed from the body for examination.

Core needle biopsy:

– A procedure which uses a special needle to cut a core of tissue for examination

Fine needle aspiration (FNAC):

– Is a cytologic procedure in which a needle is inserted into an organ or body cavity and a small sample of fluid and cells is removed.

Brush Cytology:

– Brush cytology is a technique in which a very small brush, attached to an endoscope, is used to rub off tumor cells for examination. Often used for Pancreatic and lung cancers.

Lung Biopsy – Core needle

Lung Biopsy

CT Scan of the chest with a

biopsy needle extending into a lung

mass

The needle is oriented vertically

and goes into the mass (indicated

by red color).  The lung tissue is

black and the bones are white. 

The patient is prone and the heart

is the large white structure at the

lower part of the chest.

Lung Cancer Subtypes:

• 1) Small Cell Lung Cancer

• 2) Non- Small Cell Lung Cancer

• a) Squamous b) Non- a) Squamous b) Non- SquamousSquamous

• (i) (i) Adenocarcinoma Adenocarcinoma

• (ii) Large (ii) Large Cell CarcinomaCell Carcinoma

Adenocarcinoma Cancer arising out of glandular

tissues Most frequent type diagnosed in

lung cancer (30 – 40%) Common in smokers and non-

smokers More common in women than in

men Usually arise in the peripheral

areas of lung and metastasize quickly

Bronchoalveolar carcinoma (BAC) is a subtype of adenocarcinoma and is found more in women and is associated with scars of tuberculosis

Early diagnosis is rare and prognosis is poor

Large Cell

Account for approx. 15% Progonosis same as adenocarcionoma Both ( adeno and large) are known as Non-Squamous Undifferentiated large cell, can be classified as poorly differentiated.

Squamous Cell Accounts for 30% of lung

cancers

Strongly associated with smoking

Tend to be more centrally located

Forms necrotic cavities, that can be seen on X-rays

Cell doubling rate is slow and surgical resection leads to a 30% 5 year survival rate

5 year survival rate of all SCC is 5 – 7%

Small Cell Lung Cancer (SCLC)

– Comprises 15-20% of all lung cancers

– Spreads more aggressively than NSCLC

– Is more responsive to chemotherapy

– Frequently found in smokers or former

smokers

Small Cell Lung Cancer (SCLC)

Two stages: As per Veterans Administration

Lung Cancer study group (VALCG)

Limited stage

Extensive stage

TNM staging is Now the standard after 7th

Edition 2009

Small Cell Lung Cancer (SCLC) : Sites of

metastases

SITE PERCENT

Liver 30

Bone 25

Bone marrow 20

Brain 10

Extrathoracic LN 5

Subcutaneous mass 5

Small Cell Lung Cancer (SCLC) : Paraneoplastic syndromes

More common than in NSCLC

SIADH (syndrome of inappropriate antidiuretic

hormone) : 15% of cases

Hyponatremia (low serum sodium)

Cushing’s syndrome

Neurological syndrome

Peripheral neuropathy

Eaton lambert syndrome (proximal muscle weakness)

Step by Step Approach – Advanced and Metastatic NSCLC Advanced and Metastatic NSCLC

Metanalysis BMJ 1995Pujol 2006

NSCLC: Strategies to overcome chemotherapy‘s plateau

• Novel antifolate (Alimta-Pemetrexed)

• Monoclonal antibody-targeting VEGF (Avastin-Bevacizumab)

• Monoclonal antibody-targeting EGFR (Erbitux-Cetuximab)

• Small molecules targeting EGFR (Gefitinib, Erlotinib)

• Small molecules targeting multi-TK‘s (Sorafenib, Sunitinib)

• Immune modulation targeting TLR 9 (PF-3512676)

• Vaccine targeting cancer associated MUC1-antigen (TG1410)

• Gene guided therapy (ERCC1, RRM1)

• Bisphosphonates (Zometa-Zoledronic acid)

1980’s - Advanced NSCLC

Central question in 1980’s

Does chemotherapy prolong survival in advanced stage disease?

0

2

4

6

8

10

12

Med

ian

surv

ival

(m

onth

s)1970 1980

4-6

6-8

BSC

Cisplatin based regimens

Yes, it does!Cisplatin based doublets do

Remaining issues

Toxicity -Nausea -Vomiting -Myelosuppression

3rd Generation agents

Central question in 1990’s

0

2

4

6

8

10

12

Med

ian

surv

ival

(m

onth

s)

1970 1980

4-6

6-8BSC

Cisplatin based regimens

1990

Platinum based Doublets(3rd generation)

8-10

Yes, they are!

3rd Generation agents

Vinorelbine Paclitaxel Gemcitabine Docetaxel

Are platinum based doublets with 3rd Generation agents superior to older doublets?

Central question in mid-late 90’s

Which of the new doublets was the best ?

All of them have similar efficacy and safety

ECOG 1594

Coalition

ASCO guidelineNCCN guideline

Dominant regimens in practice

US

Carboplatin based regimens

Cisplatin based regimens

EU

Mid-late 1990’s - Advanced NSCLC

Late 1990’s and 2000’s - Advanced NSCLC

Central question in late 90’s and 2000’s

Does the addition of a third agent improve efficacy to a platin- based doublet?

Yes or NO

Targeted therapy

Target several new specific targets unique or largely unique to malignant cells

Epidermal Growth Factor Receptor (EGFR)Tyrosine Kinase Inhibitors (TKI) Erlotinib Gefitinib

Result: Negative (TALENT, INTACT 1&2, TRIBUTE)

Vascular Endothelial Growth Factor (VEGF) Antibody(Anti-angiogenesis agent) Bevacizumab (Avastin)

Result:Positive (ECOG4599)

PFS advantage but no OS advantage (AVAIL)

2007 - Advanced NSCLC

Adeno Large Cell Squamous

Landmark Lilly Trial (Scagliotti et al) for the first time demonstrated a survival advantage of treatment (Pemetrexed) by histology effect

NSCLC distribution by stage and associated survival rates

NSCLCStage Distribution1

NSCLC Stage

1-Year Survival

25-Year

Survival3

I 13%–24%IA

IB

91%

72%

50%

43%

II 5%–10%IIA

IIB

79%

59%

36%

25%

III 31%–44% IIIA

IIIB

50%

37%

32%

19%

7%

IV 32%–39% IV 20% 2%

1. Bulzebruck H, et al. Cancer. 1992;70:1102-1110. 2.Mountain CF. Chest. 1997:111;1710-1717. 3. Goldstraw P. Presented at the 12th World Conference on Lung Cancer; September 5, 2007; Seoul, Korea.

Importance of Adjuvant Therapy Three randomized phase III trials and the Lung

Adjuvant Cisplatin Evaluation meta-analysis have shown a significant survival benefit for adjuvant cisplatin-based chemotherapy for selected patients with completely resected stage II and IIIA NSCLC

Postoperative adjuvant cisplatin based chemotherapy now represents the standard of care for the management of stage II to IIIA NSCLC

Adjuvant cisplatin-based chemotherapy significantly improves survival for patients with resected stage II and IIIA NSCLC

CONVENTIONAL RADIATION THERAPY

XRT, is the medical use of ionizing radiation as part of cancer treatment to control malignant cells and also for some benign ds.

The treatment by radiation is when the tumour is treated along with margin of safety with conventional dose, fractionation regimen.

CONVENTIONAL RADIATION THERAPY

What improved the results of

conventional therapy?

1. Introduction of Mega Voltage Beam.

a) Linear Accelerator – 1950 U.K.

b) Cobalt Machine - 1952 Canada

Marriage of computer science and medicine

2. Introduction of treatment planning

systems n CT in 70’s which led to better

planning and accuracy of radiation

dose delivery.

Overview-Major Milestones

3 DCRT3 DCRT

Radiation TherapyRadiation Therapy

TeletherapyCOBALT & LINACTeletherapyCOBALT & LINAC

BrachytherapyBrachytherapy

IMRTIMRT

IGRTIGRT DARTDART

Intraoperative BrachytherapyIntraoperative Brachytherapy

TomotherapyTomotherapy

Image Assisted BrachytherapyImage Assisted Brachytherapy

Stereotactic radiotherapyStereotactic radiotherapy

Gamma KnifeGamma Knife

LINAC X KnifeLINAC X Knife

CyberknifeCyberknife

NovalisNovalis

3D CRT, IMRT & IGRT

THEN NOW

What is IMRT ?Intensity Modulated Radiotherapy is a special form

of 3D-CRT in which non-uniform fluence is delivered

to the patient from any given position of the

treatment beam to optimize the composite dose

Distribution; which is calculated by an inverse

treatment planning process designed to meet

specified dosimetric objectives.

3D CRT, IMRT & IGRT

PET-CT Image fusion

3D CRT, IMRT & IGRT

Soft tissue window Lung window FDG - PET

Red outline: CT & FDG

PET provides functional information to an anatomical scan

Combined PET-CT Scanners reduce setup discrepancies

Information from PET can help modify PTV volumes

Green outline: CT only

IGRT-Image Guided RadiotherapyDART-Dynamic Adaptive Radiotherapy

Devising precise methods of delineating targets– MULTI-MODALITY IMAGING

Target Localization for verification by on-board imaging (OBI) & changing the set up accordingly

Minimizing the uncertainty due to intra-treatment motion (4D RT- Respiratory Gating)

DYNAMIC ADAPTIVE RADIOTHERAPY Two components:

Adapt to tumor motion (IGRT) Adapt to tumor / organ deformation and volume change.

3D CRT, IMRT & IGRT

3D-CRT & IMRT: Treatment Delivery & Verification

3D CRT, IMRT & IGRT

6. Match with DRRs in EPID software

5. Take Portal images

7. Final Treatment Execution

High Tech Radiotherapy MachinesHelical Tomotherapy Gamma Knife

Cyber KnifeNovalis Tx

PRECISION-A Way ForwardState Of Art Technology-NOVALIS TX

3D CRT, IMRT & IGRT

NOVALIS Tx- Precision Radiotherapy and Radiosurgery

Novalis Tx, Newest generation LINAC

Novalis Tx machine utilizes X-rays that are targeted at the tumor to destroy the growth of cell without pain and discomfort.

The Novalis TX offers the advanced definition of “multileaf collimator” (HDMLC 120). Precision 2.5 mm

3D CRT, IMRT & IGRT

The Novalis TX linear accelerator can deliver radiation in many ways

Image Guided Radiation Therapy (IGRT)

Intensity Modulated Radiation Therapy (IMRT)

EXAC TRAC Adaptive Gating  

Frameless Stereotactic Radiosurgery using High definition micro MLC (HDMLC)

Stereotactic Whole body radiation ( SBRT)

3D CRT, IMRT & IGRT

NOVALIS- Respiratory Gating Method where on-off status of treatment beam is controlled by

signals produced whenever breathing signal falls in the preset gating window

Instead of enlarging PTV to encompass the range of motion, treatment delivered only during part of the respiratory cycle.

3D CRT, IMRT & IGRT

Novalis Tx- Rapid Arc The Powerful Treatment with Novalis Tx –

Platform can deliver it quickly with the rapid arc Technology, so that patients spend little time immobilized on the treatment table. Fast treatments are easier and accurate.

3D CRT, IMRT & IGRT

NOVALIS Tx

For treatment precision – sharp, precise beams

Beam Shaper: 2.5 mm HD120® high-definition beam shaper

Gantry Precision: Mechanical accuracy throughout with 0.5 mm isocentric precision

Clinical Accuracy: Submillimeter accuracy technically & clinically demonstrated

3D CRT, IMRT & IGRT

NOVALIS Tx

For treatment power – powerful linac and advanced treatment techniques

High Dosing Delivery: Up to 1000 MU / minute dose rate

Linac MV Power: 6 MV and HighX (10-20MV) power

Flexible MV Control: RapidArc SRS/SBRS speed with power

3D CRT, IMRT & IGRT

NOVALIS Tx For tissue targeting precision - sophisticated

imaging technologies Stereo X-ray Targeting: Includes ExacTrac X-Ray 6D

and Snap verification Cone Beam CT: Includes On-Board Imager® for 3D soft

tissue target confirmation for SBRS MV Portal Vision™ and Fluoroscopy: Helps you "see

what you treat while you treat" in real time Adaptive Gating: Includes ExacTrac X-Ray 6D for

treating tumors that move with respiration Robotic Couch: Corrects patient positioning in 6D,

including pitch, roll and yaw For ease of use - intelligent & intuitive software

3D CRT, IMRT & IGRT

Novalis treats-RT, SRS, FSRS, IMRT, IGRT

Acoustic Neuromas Arteriovenous Malformation(AVM) Brain metastasis/Glioma Craniopharyngioma Spine Tumors/Metastasis Liver tumors/ Metastasis Meningioma of skull base Parkinson,s Disease Paediatric Bone Tumours Pituitary Adenomas Prostate Cancer/Metastasis Recurrent Brain Tumors Spine Tumors/Metastasis Trigeminal Neuralgia

3D CRT, IMRT & IGRT3D CRT, IMRT & IGRT

BRIGHT FUTURE AHEAD…..

Technology with lot of promises and great potentials

Turning the promises and potentials into clinical gains

– adequate infrastructure

– manpower & expertise

– Designed Depts

– understanding the limitations

3D CRT, IMRT & IGRT

RT in NSCLC: Stage Wise

Stage: I : Surgery the mainstay; SBRT

Stage II: Surgery the mainstay; SBRT

Stage III: Surgery + RT, CT + RT

Stage IV: Palliative RT

Pts. presenting with

Painful bone mets

Impending cord compression.

Brain mets

SVC obstruction/ bulky mediastinal mass

Hemoptysis

? Prophylactic cranial irradiation

CyberKnife

CyberKnife: Unique Properties

Highly precise treatment delivery

Motion management method

Tumor tracking

Dose painting

Excellent dose distribution

Fractionation schedule

No rigid fixation

Thank You

Thank YouThank You