Breakthroughs in Lung Cancer
Statistics
0072,500 new cases and 163,500 deaths
from lung cancer in the U. S. predicted for
2005.
009 deaths per hour
00ore deaths than from colon, breast,
prostate, and pancreas cancers combined
Hong, ASCO lecture, 2003
How do we improve the outcome?
00revent the disease
00iagnose earlier
00mprove treatment
Lung cancer prevention
005-90% of all lung cancer are directly
attributable to smoking (2-3% due to
second hand smoke)
00moking cessation results in significant
reductions in the risk of lung cancer in as
soon as 5 years
Lung cancer prevention
00n increased risk of lung cancer persists
for more than 20 years after smoking
cessation
00 50% of lung cancers diagnosed in former
smokers
00 number of studies ongoing to target
specific molecules that may be involved in
the development of lung cancer
Early detection (screening)
00creening is any medical activity
(examination, procedure, laboratory study)
that detects a disease (e. g. cancer) in an
asymptomatic patient
00 successful cancer screening test should
reduce mortality from that cancer in the
group that is screened
Lung cancer screening
00tudies in the 1970's and 80's suggested
that chest x-ray was not an optimal
screening test for lung cancer
Heiken et al. Radiology
1993; 189: 647
A NEW PARADIGM FOR LUNG
CANCER SCEENING
00OW DOSE HELICAL CT SCAN
-Data is obtained in a short period (10-50 seconds) of a
single or several short breath holds
-Radiation dose is less than standard CT
-Ability to reconstruct overlapping images at arbitrary
intervals allows improved lesion detection
-Relatively inexpensive
Cohort studies of helical CT
00ata from ~20,000 patients
004-51% of patients have 1 or more nodules
on baseline scan
00.3 - 2.7% of patients had biopsy after their
first CT (. 44 - . 76% after subsequent scans)
Cohort studies of helical CT
00.4% - 3.1% of patients found to have lung
cancer after the first scan
00.1 - 0.9% with lung cancer after
subsequent scans
008 - 100% of patients with cancer had
stage I disease
Helical CT
00elical CT clearly diagnoses lung cancer at
an earlier stage when compared with
conventional evaluation (? stage shift)
00resumably improves survival
00o evidence that lung cancer screening
with low-dose CT improves lung cancer
mortality
Potential harms
with lung cancer screening
00adiation exposure
00orbidity/mortality of biopsy (2-5%
mortality for thoracotomy)
00nxiety/stress of "positive" scan
00ost of initial and additional procedures
00alse reassurance
Un anticipated Benefits
00iscovery of additional cancers - (Mayo
study) - 2 carcinoids, 4 renal cell
carcinomas, 3 breast cancers, 2
lymphomas, 2 gastric tumors, 1 adrenal
cancer)
00bnormal scan as motivation - ELCAP
study found 2 fold greater rates of smoking
cessation in those with abnormal scans
Lung Screening Study
00CI trial of spiral CT or CXR in patients
ages 55-74 with significant smoking history
00ost - 200 million dollars
00ompleted accrual (50,000 patients)
00uration 7 years
00owered to detect 20% reduction in
mortality with annual screening
Breakthroughs in the treatment
of lung cancer
Adjuvant therapy for lung cancer
00djuvant therapy - treatment (e. g.
chemotherapy) after surgery to eliminate
microscopic residual cancer and prevent
cancer recurrence
00ntil recently, adjuvant therapy was felt to
have no role in lung cancer
Treatment for advanced lung cancer
00or patients with advanced (metastatic)
disease, chemotherapy improves survival
and quality of life (but does not cure)
00ven with treatment, only 35-40% of
patients survive one year and fewer than
10% survive 2 years
00ore effective options are clearly needed
Alimta: helping patients with
malignant pleural mesothelioma
00limta is a chemotherapy drug that was approved
in February 2004 for malignant pleural
mesothelioma, a very rare, very aggressive form
of lung cancer
00limta extended the life of mesothelioma patients
by 30% when it was added to cisplatin, another
chemotherapy drug
00his is the first and only chemotherapy drug to
receive FDA approval for the treatment of
mesothelioma
Alimta now approved
for recurrent lung cancer
00ater in 2004, Alimta was approved for use in advanced
stage NSCLC, a common type of lung cancer
00sed by itself, Alimta was compared to Taxotere, another
approved chemotherapy drug, in patients who had already
received therapy for their lung cancer
00hile patients taking Alimta and Taxotere had similar
survival, patients on Alimta had fewer/less severe side
effects, including low white blood cell counts, infection,
diarrhea, hospitalization, and hair loss
00hese results led to Alimta's approval for patients with
advanced NSCLC
Biological targets
for cancer therapy
Tumor cell
4. Proteasome
1
2
3
4
5
6
1. Growth factors and
growth-factor receptors
HER family, VEGF/R, c-kit/SCFR
2. Signal-transduction pathways
Ras, raf, MAPK, MEK, ERK,
protein kinase C, PI3K
3. Tumor -associated
antigens/markers
Gangliosides, CEA,
MAGE,
CD20, CD22
6. Extracellular matrix/
angiogenic pathways
MMPs, VEGF, integrins
5. Cell-survival pathways
Cyclin-dependent kinases,
mTOR, cGMP, COX-2, p53, Bcl-2
Ullrich A. Oncology 2002; 63 (Suppl. 1) : 1-5
Proposed Mechanism of Action of
EGFR-Targeted Tyrosine Kinase Inhibitors
BCL2 00BA X 00/span>
Phosphorylation
No
signaling
Growth arrest
TK Is
Tumor cell
proliferation
PI 3K
MAP K
Tumor cell
survival
Cell death
P
P
P
P
M
G
1
S
G
2
Inhibits EGFR
kinase activity
Moyer et al. Cancer Res . 1997; 57: 4838.
Tarceva and Iressa
00ral EGFR tyrosine kinase inhibitors
00ave activity in non-small cell lung cancer (~10-
15% of tumors will shrink; ~30-40% will be
stable)
00arceva improves survival in patients with
metastatic disease that have failed first-line
chemotherapy
00ccasional dramatic and durable tumor responses
are seen
Avastin
00onoclonal antibody to VEGF
00revents cancers from developing their blood supply
00n a study of over 800 patients with advanced lung cancer
who received chemo with or without Avastin:
-Only 10% of patients on chemo only had significant tumor
shrinkage, compared to 27% of those who added Avastin
-Avastin appears to improve survival when given with chemo
(average of 12.5 months with Avastin, 10.2 months without it)
00ay be FDA approved for lung cancer in the near future
Breakthroughs in lung cancer
00moking cessation remains the only proven
effective way to reduce the risk of lung
cancer
00 number of other "molecularly targeted"
drugs are being actively investigated as
preventative agents
Breakthroughs in lung cancer
00arly detection with helical CT holds
promise of decreasing mortality from lung
cancer
00ew therapies for advanced lung cancer
have led to incremental improvements in
the survival in this population
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