Eva-Szabo
Document Sample
Non-small Cell Lung Cancer
Eva Szabo, MD
Division of Cancer Prevention, NCI
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
Age-adjusted lung cancer death rates, USA
(1930-1998)
Rate per 80
100,000 Lung and bronchus (male)
Lung and bronchus (female)
male/female
population
60
40
20
0
1930 1940 1950 1960 1970 1980 1990
Five-year survival by TNM status in
NSCLC
Stage TNM classification 5-year survival
(%)
IA T1N0M0 61
IB T2N0M0 38
IIA T1N1M0 34
IIB T2N1M0 or T3N0M0 24
IIIA T1-3N2M0 orT3N1M0 13
IIIB T4NanyM0 or Tany N3M0 5
IV Tany NanyM1 1
Mountain 1997
Risk Factors
• Tobacco, tobacco, tobacco (85% lung ca.)
• Other exposures
– Asbestos, radon, polycyclic aromatic
hydrocarbons, chromium, nickel, inorganic
arsenic
– Passive smoking
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%
Sequential changes during lung cancer pathogenesis
Early Intermediate Late
Normal Invasive
Hyperplasia Dysplasia CIS
epithelium carcinoma
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
• 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
• 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 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
• Prevention (primary, secondary, tertiary)
• Early detection
• Better therapeutics-novel targeted agents
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
-modified from
Peto et al.,
BMJ 321:323, 2000
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
Chemoprevention Chemotherapy
Target • Cured cancer patient • Cancer patient
• Pre-cancer patient
• Genetically
predisposed
End- • Cancer development • Eradicate cancer
point • Phenotype reversal • Control/palliate
Agent • Minimal toxicity • Moderate toxicity
• Potentially long term • Usually short term
Field Cancerization
Multifocal Clonal Expansions Second primary tumors
Metaplasia
First Second
Carcinoma Primary
Primary
Dysplasia
Hyperplasia
Third
Primary
Evolution of Intraepithelial Neoplasia
Normal Hyperplasia/Metaplasia Dysplasia Cancer
Mild/Moderate/Severe/CIS
Squamous
Adenomatous
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
• 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)
• 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
• 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 III Lung Chemoprevention Trials
ATBC 29,133 -carotene 18% risk
1994 smokers +/- vit E lung ca.
CARET 18,314 -carotene + Inc risk lung
1996 Smokers or retinol ca RR=1.36
asbestos
EUROSCAN 2592 lung, Retinyl palm No benefit
2000 H&N ca +/- NAC
Intergroup 1265 lung 13-cRA No benefit
2001 ca
Phase II Lung Chemoprevention Trials
Investigator Agents Endpoint Outcome
Arnold Etretinate Sputum Atypia Negative
Lee 13cRA Metaplasia Negative
Kurie 4-HPR Metaplasia Negative
McLarty -carot/Retinol Sputum Atypia Negative
Pastorino Retinol Palmit Lung Cancer Positive
Kurie 9cRA vs. 13cRA+ RAR-beta RAR-
Vit E with 9cRA
Lam Anethole dithiole Bronchial New
thione dysplasia lesions
Critical Components of Clinical Trials
Cohorts: Endpoints:
High risk Cancer-related
Likely to respond Drug effect markers
Design/Execution
Agents:
Target
Dose, schedule, route, duration
Efficacy vs. side effects
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
• 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
• 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
• Dose, route, schedule
• Approved vs. experimental
• Risk/benefit ratio
– Importance of cohort risk
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
Apoptosis
Normal Preneoplastic Differentiation
cell cell
Growth
Angiogenesis
Invasion
Arachidonic Acid Metabolism
A Novel Target for Aerodigestive Chemoprevention
Membrane Phospholipids
Steroids PLA2
Arachidonic Acid
5-LO Inh LO COX NSAIDs
Zileuton
HPETEs PGG2
Zileuton LO
HETEs LTs PGH2
Prostaglandins
Effect of Budesonide on Mouse
Lung Tumorigenesis
-82% inhibition
-Pereira et al.
Carcinogenesis 2002
Shift from Carcinoma to Adenoma
by Budesonide
Pereira et al.,
Carcinogenesis
2002
Potential Mechanism of Action of
Budesonide: Induction of CDK
Inhibitors
Pereira et al.,
Carcinogenesis
2002
DCP Phase IIb Trial of
Budesonide
S. Lam, BCCA
115 smokers with dysplasia
(Bronch)
(Spiral CT) # Screened (sputum): 1043
# Dropped out (Rx): 15
Budesonide vs. Placebo x 6mths Cancers detected: 13
(3.1%)
(Bronch,
Spiral CT)
1o Endpoint: bronchial dysplasia (#sites/grade)
2o Endpoints: multiple biomarkers
Effect of Budesonide on Bronchial
Histology
60
50
40
% 30 Placebo
Budesonide
20
10
0
CR PR SD PD
Effect of Budesonide on Spiral CT-
Detected Peripheral Nodules
Outcome Placebo Budesonide
# Nodules # Nodules
(% total) (% total)
Unchanged 102 (87%) 43 (72%)
Resolved 14 (12%) 16 (27%)*
or smaller
Follow-up 1 (1%) 1 (1%)
pending
* P=0.024
Arachidonic Acid Pathway:
Lipoxygenase Branch
Catalyzed by 5-Lipoxygenase:
COOH
Arachidonic Acid
O2 arachidonate
OOH
5,12,15 LOs
12-HPETE 15-HPETE COOH
5-HPETE
5-HPETE H2O
O
COOH
LTs 5-HETE leukotriene-A4
Decrease in Tumor # and Size by
Leukotriene 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
Carcinomas by
50 %
Inhibits: 5-LO FLAP LTD4
DCP Phase IIb Trial of Zileuton
O. 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:
Cross-over x 6 mths (Bronch) multiple biomarkers
Agents currently under development
• 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
Combination
Chemoprevention
-Increase efficacy
-Reduce toxicity
(lower doses)
Aerosolized delivery to
minimize systemic toxicity
“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
• 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
Spiral CT for Early Lung Cancer
Detection
• 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
Study #Subjects %Positive # Cancers Stage I
ELCAP 1,000 23% 27 (prev) 85%
(Henschke et al.,
1999)
Mayo 1,520 66% 23 (prev 57%
(Swensen et al., & inc)
2002)
Japan 1,611 11.5% 14 (prev) 71%
(Sobue et al., 22 (inc) 82%
2002)
Ongoing NCI-Sponsored Lung Cancer
Screening Studies
• 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)
“An ounce of prevention
is worth a pound of cure”
-Benjamin Franklin
