Non small cell lung cancer
Download
1 / 50

Non-small Cell Lung Cancer - PowerPoint PPT Presentation


  • 407 Views
  • Uploaded on

Small cell lung cancer: chemotherapy (+radiation for limited stage) ... Decline in California lung cancer rates 1988-1997 declined 14%, compared with ...

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Non-small Cell Lung Cancer' - Kelvin_Ajay


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
Non small cell lung cancer l.jpg

Non-small Cell Lung Cancer

Eva Szabo, MD

Division of Cancer Prevention, NCI


Us lung cancer statistics 2003 l.jpg
US Lung Cancer Statistics, 2003

  • 171,900 estimated new cases

  • 157,200 estimated deaths

    • 88,400 men and 68,800 women

  • leading cause of cancer deaths

    • greater than breast+prostate+colon

  • 15% five year survival

    • 5% in 1950’s, 13% in 1970’s


Slide3 l.jpg

Age-adjusted lung cancer death rates, USA (1930-1998)

80

Rate per 100,000 male/female population

Lung and bronchus (male)

Lung and bronchus (female)

60

40

20

0

1930

1940

1950

1960

1970

1980

1990


Slide4 l.jpg

Five-year survival by TNM status in NSCLC

Stage

IA

IB

IIA

IIB

IIIA

IIIB

IV

TNM classification

T1N0M0

T2N0M0

T1N1M0

T2N1M0 or T3N0M0

T1-3N2M0 orT3N1M0

T4NanyM0 or TanyN3M0

TanyNanyM1

5-year survival (%)

61

38

34

24

13

5

1

Mountain 1997


Risk factors l.jpg
Risk Factors

  • Tobacco, tobacco, tobacco (85% lung ca.)

  • Other exposures

    • Asbestos, radon, polycyclic aromatic hydrocarbons, chromium, nickel, inorganic arsenic

    • Passive smoking


Pathology l.jpg
Pathology

  • Non-small cell lung cancer

    • Adenocarcinoma, inc bronchoalveolar 40%

    • Squamous cell carcinoma 20%

    • Large cell carcinoma 15%

    • Others (carcinoid, etc.)

  • Small cell lung cancer 20%


Slide7 l.jpg

Sequential changes during lung cancer pathogenesis

Early Intermediate Late

Normal epithelium

Invasive carcinoma

Hyperplasia

Dysplasia

CIS

3p LOH/small telomeric deletions

3p LOH/contiguous deletions

~80%

Microsatellite alterations

~50%

9p21 LOH

~70%

Telomerase dysregulation

Telomerase upregulation

~80%

myc overexpression

~60%

8p21-23 LOH

~80%

Neoangiogenesis

~40%

Loss of Fhit immunostaining

~40%

p53 LOH

p53 mutations

~70%

Aneuploidy

~80%

Methylation

~100%

5q21 APC-MCC LOH

~30%

K-ras mutation

~20%

Hirsch et al 2001


Treatment strategies for lung cancer l.jpg
Treatment Strategies for Lung Cancer

  • NSCLC: Treatment based on stage:

    • Early stage (Stage I/II) – surgery

    • Regional spread –combined modality (chemoradiation)

    • Metastatic – chemotherapy, radiation as needed for local control

  • Small cell lung cancer: chemotherapy (+radiation for limited stage)


Controversies in nsclc treatment l.jpg
Controversies in NSCLC Treatment

  • Adjuvant therapy

    • IALT study – small, but real (4.1%) improvement in survival with 3-4 cycles cisplatin (ASCO 2003)

    • UFT x 2 yrs in stage I adenoca – 2.5% improvement in survival (ASCO 2003)

  • Neoadjuvant therapy

    • BLOT-phase II study, stage Ib-IIIA, induction taxol/carbo followed by surgery post-op chemo, 3 yr survival 63% superior to historical control (J Thor Cardio Surg 119:429, 2000)

  • Adjuvant radiation

    • PORT meta-analysis – not for early stage, probably not for regional disease (Lancet 352:257, 1998)


Controversies in nsclc treatment10 l.jpg
Controversies in NSCLC Treatment

  • Choice of agents?

    • Platinum vs. not (probably yes)

    • Single vs. two vs. three agents (probably 2)

  • Treatment of elderly – Yes if good performance

  • Length of treatment – probably no more than 6 cycles of cytotoxic conventional chemo

  • Second line treatment – yes

    • Taxotere better than supportive care

    • Iressa (EGFR inhibitor) approved after cisplatin/taxotere failure


Approaches to reducing cancer morbidity and mortality l.jpg
Approaches to reducing cancer morbidity and mortality

  • Prevention (primary, secondary, tertiary)

  • Early detection

  • Better therapeutics-novel targeted agents


Primary prevention l.jpg
Primary Prevention

  • Smoking cessation

    • Decline in California lung cancer rates 1988-1997 declined 14%, compared with 2.7% in non-California SEER sites, coincident with declining smoking rates probably due to California tobacco control initiatives

      • Cowling DW et al., MMWR 49:1066-9, 2000


Lung cancer risk after smoking cessation l.jpg
Lung Cancer Risk After Smoking Cessation

-modified from

Peto et al.,

BMJ 321:323, 2000


Cancer chemoprevention l.jpg
Cancer Chemoprevention

The use of natural or synthetic agents to

suppress or reverse carcinogenesis

  • Regress existing neoplastic lesions (treat intraepithelial neoplasia)

  • Prevent development of new neoplastic lesions (preneoplastic and cancer)

  • Suppress recurrence of neoplastic lesions


Cancer prevention vs treatment l.jpg

Cured cancer patient

Pre-cancer patient

Genetically predisposed

Cancer development

Phenotype reversal

Minimal toxicity

Potentially long term

Cancer patient

Eradicate cancer

Control/palliate

Moderate toxicity

Usually short term

Cancer Prevention vs. Treatment

ChemopreventionChemotherapy

Target

End-

point

Agent


Field cancerization l.jpg
Field Cancerization

Multifocal Clonal Expansions

Second primary tumors

Metaplasia

First Primary

Second Primary

Carcinoma

Dysplasia

Hyperplasia

Third Primary


Evolution of intraepithelial neoplasia l.jpg
Evolution of Intraepithelial Neoplasia

Normal Hyperplasia/Metaplasia DysplasiaCancer

Mild/Moderate/Severe/CIS

Squamous

Adenomatous


Natural history of bronchial atypia l.jpg
Natural History of Bronchial Atypia

  • Progression to cancer based on sputum analysis

    • Moderate dysplasia: 11%

    • Severe dysplasia: 19-46%

  • Progression to cancer based on bronchoscopic dx, 2-3 yr f/u (Bota et al., 2001; Venmans et al., 2000)

    • Normal/inflammatory: 16% became dysplastic

    • Hyperplasia/metaplasia: 37% regress, 2% cancer at 2 yrs

    • Low or moderate dysplasia: 37% regress, 3.5% severe dysplasia

    • Severe dysplasia: 41% regress to normal, 37% remain or progress

    • Carcinoma in situ: 56% progress at site (44% also had severe dysplasia or CIS elsewhere)


Natural history of atypical alveolar hyperplasia l.jpg
Natural History of Atypical Alveolar Hyperplasia

  • Unknown at the current time

  • Localized ground glass opacities on CT:

    • Fibrosis 15%; AAH 25%; bronchoalveolar ca 50%; invasive adenoca 10% (Nakajima et al., J Comput Assist Tomogr 2002)


Oral leukoplakia hong et al nejm 1986 l.jpg
Oral Leukoplakia(Hong et al., NEJM 1986)

  • 44 pts., 3 mths high dose 13cRA vs. placebo

    • Response: decreased size in 67% vs. 10% placebo

    • Response: reversed dysplasia 54% vs. 10% placebo

    • Relapse in >50% pts; toxicity high

  • F/U study (Lippman et al., NEJM 1993)

    • 3 months high dose 13cRA followed by low dose maintenance is better than -carotene maintenance


Prevention of second primary cancers head neck l.jpg
Prevention of Second Primary CancersHead & Neck

  • Hong et al., 1990 NEJM: 103 pts., 12 months of isotretinoin (13cRA) high dose after curative therapy for H & N ca.

  • Results:

    •  second primary tumors (4% vs. 24%, 32 mths)

    • no survival advantage; toxicity

  • Khuri et al., Proc ASCO 2003:1190 stage I/II H & N ca pts., low dose 13cRA for 3 yrs

    • No effect on second primaries or overall survival



Phase ii lung chemoprevention trials l.jpg

Investigator

Arnold

Lee

Kurie

McLarty

Pastorino

Kurie

Lam

Phase II Lung Chemoprevention Trials

Agents

Etretinate

13cRA

4-HPR

-carot/Retinol

Retinol Palmit

9cRA vs. 13cRA+

Vit E

Anethole dithiole thione

Endpoint

Sputum Atypia

Metaplasia

Metaplasia

Sputum Atypia

Lung Cancer

RAR-beta

Bronchial dysplasia

Outcome

Negative

Negative

Negative

Negative

Positive

RAR- 

with 9cRA

 New lesions


Critical components of clinical trials l.jpg
Critical Components of Clinical Trials

Cohorts:

High risk

Likely to respond

Endpoints:

Cancer-related

Drug effect markers

Design/Execution

Agents:

Target

Dose, schedule, route, duration

Efficacy vs. side effects


Cohorts l.jpg
Cohorts

  • Heavy smokers (current vs. former)

    • Lifetime risk lung cancer: 1% for 20 pack-yrs; 5% for 60-pack yrs.; 13% for 100 pack-yrs.

  • Curatively treated early stage tobacco-related cancer patients

    • Stage I NSCLC (5 yr surv: >70% for T1; 60% T2)

    • Stage I/II H & N ca (80% 5 yr survival)

    • High rate of second primaries (1-3%/yr)


Emerging concepts target population former smokers l.jpg
Emerging Concepts Target Population: Former Smokers

  • 50% of lung cancers are in former smokers

  • Biologic differences between current and former smokers

    • extent of DNA damage, histologic abnormalities

  • Adverse outcome in current, but not former, smokers in prior phase III studies

    • -carotene in ATBC/CARET

    • 13-cis retinoic acid in Intergroup Study

  • Positive outcome more likely in former smokers without ongoing DNA damage


Potential endpoints l.jpg
Potential Endpoints

  • Histologic preneoplastic lesions

  • Proliferative indices

  • Apoptotic indices

  • Differentiation markers

  • Other carcinogenesis-related markers/processes (e.g., oxidative stress, oncogenes, methylated genes)

  • Drug effect biomarkers

Question: How can these help us determine whether to

continue with drug development?


Agents l.jpg
Agents

  • Dose, route, schedule

  • Approved vs. experimental

  • Risk/benefit ratio

    • Importance of cohort risk


New agent identification l.jpg
New Agent Identification

  • Mechanism

  • Preclinical supportive data

    • Cell line studies

    • Animal carcinogenesis models

  • Epidemiologic data (case-control, cohort)

  • Secondary endpoints from clinical trials


Mechanisms of action of chemopreventive agents l.jpg
Mechanisms of Action of Chemopreventive Agents

Apoptosis

Normal

cell

Preneoplastic

cell

Differentiation

Growth

Angiogenesis

Invasion


Arachidonic acid metabolism a novel target for aerodigestive chemoprevention l.jpg
Arachidonic Acid MetabolismA Novel Target for Aerodigestive Chemoprevention

Membrane Phospholipids

PLA2

Arachidonic Acid

LOCOX

HPETEsPGG2

LO

HETEsLTsPGH2

Prostaglandins

Steroids

5-LO Inh

Zileuton

NSAIDs

Zileuton


Effect of budesonide on mouse lung tumorigenesis l.jpg
Effect of Budesonide on Mouse Lung Tumorigenesis

-82% inhibition

-Pereira et al.

Carcinogenesis 2002


Shift from carcinoma to adenoma by budesonide l.jpg
Shift from Carcinoma to Adenoma by Budesonide

Pereira et al.,

Carcinogenesis

2002


Potential mechanism of action of budesonide induction of cdk inhibitors l.jpg
Potential Mechanism of Action of Budesonide: Induction of CDK Inhibitors

Pereira et al.,

Carcinogenesis

2002


Dcp phase iib trial of budesonide s lam bcca l.jpg
DCP Phase IIb Trial of Budesonide CDK InhibitorsS. Lam, BCCA

115 smokers with dysplasia

(Bronch)

# Screened (sputum): 1043

# Dropped out (Rx): 15

Cancers detected: 13 (3.1%)

(Spiral CT)

Budesonide vs. Placebo x 6mths

(Bronch,

Spiral CT)

1o Endpoint: bronchial dysplasia (#sites/grade)

2o Endpoints: multiple biomarkers



Effect of budesonide on spiral ct detected peripheral nodules l.jpg

Outcome CDK Inhibitors

Placebo

# Nodules

(% total)

Budesonide

# Nodules

(% total)

Unchanged

102 (87%)

43 (72%)

Resolved or smaller

14 (12%)

16 (27%)*

Follow-up pending

1 (1%)

1 (1%)

Effect of Budesonide on Spiral CT-Detected Peripheral Nodules

* P=0.024


Arachidonic acid pathway lipoxygenase branch l.jpg
Arachidonic Acid Pathway: CDK InhibitorsLipoxygenase Branch

Arachidonic Acid

5-HPETE

LTs 5-HETE

5,12,15 LOs

12-HPETE 15-HPETE


Decrease in tumor and size by leukotriene inhibitors gunning et al cancer res 62 4199 2002 l.jpg
Decrease in Tumor # and Size by Leukotriene Inhibitors CDK Inhibitors-Gunning et al., Cancer Res 62:4199, 2002

  • Inhibition of Tumor #

  • Accolate (LTD4 inhibitor): 29.5%

  • Zileuton (5-LO inhibitor): 28.1%

  • MK866 (FLAP inhibitor): 37.8%


Decrease in carcinoma by leukotriene inhibitors gunning et al cancer res 62 4199 2002 l.jpg
Decrease in Carcinoma # by Leukotriene Inhibitors CDK Inhibitors-Gunning et al., Cancer Res 62:4199, 2002

  • Carcinomas by

    50 %

Inhibits: 5-LO FLAP LTD4


Dcp phase iib trial of zileuton o kucuk wayne state l.jpg
DCP Phase IIb Trial of Zileuton CDK InhibitorsO. Kucuk, Wayne State

134 smokers with dysplasia

(Bronch)

Zileuton vs. Placebo x 6 mths (Bronch)

1o Endpoint:

bronchial dysplasia

(#sites/grade at 6 mths)

2o Endpoints:

multiple biomarkers

Cross-over x 6 mths (Bronch)


Agents currently under development l.jpg
Agents currently under development CDK Inhibitors

  • Inhaled budesonide

  • Zileuton (5-lipoxygenase inhibitor)

  • Celecoxib, rofecoxib (COX-2 inhibitor)

  • Pioglitazone (PPAR agonist)

  • Green tea polyphenols

  • ACAPHA (herbal extract)

  • Myo-inositol (dietary supplement)

  • Selenium

  • Sulindac sulfone (Exisulind)


Emerging concepts regional drug delivery combinations l.jpg
Emerging Concepts: CDK InhibitorsRegional Drug Delivery, Combinations

Combination

Chemoprevention

-Increase efficacy

-Reduce toxicity

(lower doses)

Aerosolized delivery to

minimize systemic toxicity


Slide44 l.jpg

“For it happens…that in the beginning of the malady it is easy to cure but difficult to detect, but in the course of time, not having been either detected or treated in the beginning, it becomes easy to detect but difficult to cure.”-N. Machiavelli, The Prince


Issues in lung cancer screening l.jpg
Issues in Lung Cancer Screening is easy to cure but difficult to detect, but in the course of time, not having been either detected or treated in the beginning, it becomes easy to detect but difficult to cure.”

  • Lead-time bias=earlier diagnosis but no postponement of death (survival appears longer)

  • Length bias=diagnosis of more indolent disease with longer preclinical phase (better prognosis, better outcome)

  • Overdiagnosis=identification of clinically unimportant lesions that would not be diagnosed otherwise

  • Morbidity/mortality/cost of screening and subsequent work-up


Lung cancer screening trials x ray sputum cytology l.jpg
Lung Cancer Screening Trials is easy to cure but difficult to detect, but in the course of time, not having been either detected or treated in the beginning, it becomes easy to detect but difficult to cure.”X-ray, Sputum Cytology


Spiral ct for early lung cancer detection l.jpg
Spiral CT for Early Lung Cancer Detection is easy to cure but difficult to detect, but in the course of time, not having been either detected or treated in the beginning, it becomes easy to detect but difficult to cure.”

  • ELCAP (Henschke et al., Lancet, 1999)

    • low dose spiral CT in 1000 asymptomatic smokers

    • results:

      • 2.7% lung cancers diagnosed by CT vs. 0.7% by CXR

      • 85% cancers were stage I vs. 22% expected

      • 96% were resectable


Spiral ct screening trials l.jpg
Spiral CT Screening Trials is easy to cure but difficult to detect, but in the course of time, not having been either detected or treated in the beginning, it becomes easy to detect but difficult to cure.”

Study #Subjects %Positive # Cancers Stage I


Ongoing nci sponsored lung cancer screening studies l.jpg
Ongoing NCI-Sponsored Lung Cancer Screening Studies is easy to cure but difficult to detect, but in the course of time, not having been either detected or treated in the beginning, it becomes easy to detect but difficult to cure.”

  • PLCO

    • 74,000 men/women

    • Age 55-74

    • CXR vs. none (prevalence, then x3)

  • NLST

    • 50,000 smokers (current and former)

    • Age 55-74

    • Spiral CT vs. chest –Xray (prevalence, then x2)


Slide50 l.jpg

“An ounce of prevention is easy to cure but difficult to detect, but in the course of time, not having been either detected or treated in the beginning, it becomes easy to detect but difficult to cure.”

is worth a pound of cure”

-Benjamin Franklin


ad