Transcript ASCO_2010_files/Bendell Epidem EsophGastr ca ASCO 2010

Understanding the
evolution in the
epidemiology of
esophagogastric cancers
Johanna Bendell, MD
Director, GI Oncology Research
Sarah Cannon Research Institute
Learning Objectives
After reading and reviewing this material, the participant
should be better able to:
• Describe the changing epidemiology of esophagogastric
cancers
• Understand that the evolving epidemiology translates
into a shifting biology of these cancers
• Identify how the difference in biology effects treatment
options and research on new agents for these cancers
Esophageal Cancer Incidence
• U.S. 2009
–
–
–
–
–
16,470 new cases, 14,530 deaths
3-6 cases per 100,000
89% fatality rate
Over 50% adenocarcinoma
Until 1970’s >90% was SCC
• Worldwide
– 7th leading cause of cancer death
– Higher rates (30-800 cases per 100,000) seen in
Northern Iran, Southern Russia, and Northern China
– Remains 95% SCC
Annual Prevalence of
Esophageal Cancer
Middle East and Northern Africa
Women
Men
South-Eastern Asia
Latin America and Carribbean
Oceania
Eastern Europe
Sub-Saharan Africa
North America
South-Central Asia
Western Europe
Japan
China, Korea, Mongolia
0
1
2
3
4
5
6
Cases / 100,000
7
8
9
Pisani, 2001
Common worldwide risk factors
•
•
•
•
•
•
•
•
•
•
•
•
•
Smoking
EtOH
Opium
Mate (hot or cold)
Pickled vegetables
Polycyclic aromatic hydrocarbons
N-nitroso compounds
Achalasia
Poor oral hygiene and tooth loss
Nutrient deficiencies – selenium, zinc
Medications
Socioeconomic status
Protective effect of NSAIDS
Esophageal cancer histology
• SEER database data, 19752004
• White males
– 463% increase in incidence
of adenocarcinoma
– 1.01/100,00 to
5.69/100,000
– 50% decrease in SCC
• White females
– 335% increase in incidence
of adenocarcinoma
– 0.17/100,000 to
0.74/100,000
– 29% decrease in SCC
Reproduced with permission
Brown, et al. JNCI 2008
Distribution of esophageal
cancer by segment
Segment
Upper
Third
Middle
Third
Lower
Third
Overlapping
SCC
Male
19%
SCC
Female
20%
ADC
Male
2%
ADC
Female
4%
40%
47%
13%
18%
35%
28%
80%
73%
6%
6%
5%
5%
What happened???
Adenocarcinoma
Squamous Cell Carcinoma
Adenocarcinoma
Squamous Cell Carcinoma
16
14
12
10
8
6
4
2
0
0
20-29 30-39 40 +
0
3.5
11
14.5
25
28.5
36+
Drinks per Week
Cigarettes per Day
Quitting Smoking and Esophageal Cancer
6
O
d
d
s
5
4
3
R
a
t
i
o
2
1
C
24 20
+
ev y e
er ar
Sm s
ok
er
18
15
10
8
5
1.
5
2.
5
Years Since Quitting
Data from Wu, 2001
and Castellsague, 2000
N
sm
ok
er
0
ur
r
– Tobacco increases
risk of SCC by 3-7
fold, adenoca by 2
fold
– EtOH increases risk of
SCC only (3-5 fold, 3+
drinks/day)
18
en
t
• “Traditional” risk
factors for
esophageal cancers
• Tobacco and EtOH
Takezaki 2000, Wu 2001, Brown 2001, Kamangar 2009
Increases in risk factors for
esophageal adenocarcinoma
• Obesity
– Increases risk of adenoca
2-3 fold
– Increasing rates of obesity
in U. S. and other Western
countries
– Linked to increase in
GERD/Barrett’s via
increased intra-abd
pressure, increased levels
of gherlin, IGF, and others
3
Squamous Cell
2.5
Adenocarcinoma
2
1.5
1
0.5
0
I (low)
II
III
BMI, Quartile
Chow 1998, Abnet 2008, Corley
2008+2007, Edelstein 2007
IV
Increases in risk factors for
esophageal adenocarcinoma
• GERD
– Increased risk with duration
and frequency
– 8-20 fold increased risk
• Barrett’s esophagus
– Development of Barrett’s
metaplasia associated with
GERD, inflammation,
oxidative stress
– Metaplasia transforms to
dysplasia and then to
adenoca at rate of 0.5%/year
Barrett’s Esophagus
Lagergren 1999
Increases in risk factors for
esophageal adenocarcinoma
• H. pylori infection
• Protective against esophageal adenocarcinoma
– Colonization associated with 50% risk reduction
– Decreased acid production
– Decreased ghrelin
• Increased sanitation and increased antibiotics
– H. pylori now present in only 5% of children born in
the 1990’s in the U. S.
Chow 1998, Wren 2007, Kamangar 2007, Chen 2008
Gastric Cancer Incidence
• U.S. 2009
– 21,130 new cases, 10,620 deaths
– 10 cases per 100,000
– 50% fatality rate
• Worldwide
– 3th leading cause of cancer death
– Highest rates in Eastern Asia, Andes region
of South America, Eastern Europe (70 cases
per 100,000)
– Incidence worldwide is rapidly declining
How does gastric cancer
compare to esophageal
• Rates of gastric
cancer?
cancer are actually
declining
– Worldwide effect
Reproduced with permission
El-Serag, et al. Gut 2002
Rates of esophageal and gastric
cancers in the U. S.
• For gastric cancer,
over time incidence is
stable across all
groups
– Race
– Gender
Reproduced with permission
El-Serag, et al. Gut 2002
Gastric cancer types
• Intestinal type
– Well-differentiated
– Related to gastritis, gastric atrophy, intestinal metaplasia
– More common in in older men, East Asia, Eastern Europe,
Central and South America
– Decreasing incidence
• Diffuse type
–
–
–
–
–
Undifferentiated
Related to pangastritis
More common in younger patients, M = F
Increasing incidence
Worse prognosis
Gastric cancer by location
• Gastric cardia tumors
– Rapidly increasing incidence
– Correlates with the increasing incidence of
esophageal and GE junction adenocarcinoma
– Poorer prognosis than distal stomach
– Shares demographic and pathologic features of
Barrett’s-associated esophageal cancer
– Not associated with atrophic gastritis and intestinal
metaplasia
– Different genetic polymorphisms seen between
cardia and non-cardia tumors, suggesting they have
different biology
El-Serag 2002, Powell 1992
Traditional risk factors
• Preserved foods
– Salt and N-nitroso compounds
– Mucosal damage, carcinogenic
– Decreased incidence with widespread refrigeration
• Fresh fruits and vegetables
– High intake of fruits and vegetable protective
• Smoking
• Others
– Pernicious anemia, blood type, HNPCC, EBV, etc
The H. pylori effect
• H. pylori colonization associated with
atrophic gastritis, intestinal metaplasia,
and non-cardia gastric adenocarcinoma
– H. pylori inhibits secretion of ascorbic acid, which
scavenges N-nitroso compounds and free radicals
• Decline in H. pylori colonization correlates
with increase in gastric cardia cancers
– Further suggestion of similarity of gastric cardia, GE
junction, and distal esophageal adenocarcinomas
Hansen 1999, Chow 1998, Sanduleanu 2001
What is changing?
• Refrigeration
• Increased rates of obesity
– As with increasing esophageal and GE
junction adenocarcinomas
– Increased reflux associated with increased
gastric cardia cancer
• H. pylori
So where are we now?
• Increasing rates of obesity, gastroesophageal
reflux disease, and decline in H. pylori
colonization appear to be associated with recent
increases in esophageal cancers and gastric
cardia cancers
• The more historical esophageal and gastric
cancers (SCC and distal gastric cancers) are
declining
• What does this mean for interpretation of older
trial data that is the basis for how we treat these
tumors?
Are we treating different
tumors the same?
• How does the biology of SCC cancers and
adenocarcinomas differ?
– Risk factors are different
• Tobacco/preserved foods vs. Obesity/GERD
– Steps in carcinogenesis different
– Patient populations different
• Co-morbidities
– SCC’s have higher postop mortality
– SCC’s recur locally, adeno’s distantly
– Adeno prognosis better in early disease
Are we treating different
tumors the same?
• Many studies have combined SCC and
adenocarcinoma populations
• Data we have to try to differentiate
treatment outcomes mostly from metaanalyses
Are we treating different tumors
the same?
• Chemotherapy plus surgery
– SCC
• 2 Western studies (MRC OEO-2, Kelsen) included SCC patients
• JCOG 8806/JCOG 9204 (postop chemo), JCOG 9907 (preop vs.
postop)
– Postop and preop chemo show no OS benefit (though N+ pts
trended towards benefit)
– Preop > postop, though >50% of postop pts did not receive rx,
and N0 pts excluded from postop arm
• Meta-analysis (Thirion)
– Thirion - 4% improvement in OS at 5 years
– Gebski – no improvement in OS at 2 years
• Chemo alone not recommended for SCC
– Adenocarcinoma
• MRC OEO-02, MAGIC, FFCD – all with 14% improvement in OS
• Meta-analysis (Thirion) – 7% improvement in OS at 5 years
Chemoradiation plus surgery
Multiple analyses
- Most suggest benefit of
-
-
-
-
chemoradiation therapy
Geh, et al.
Meta-analysis
pCR 25% SCC 17% adeno
Gebski, et al.
Meta-analysis
SCC and adeno both with
HR 0.75-0.84
Bollschweiler, et al.
Retrospective review
SCC and adeno similar OS and
pCR
Less adenos respond to CRT, but
those with major response do
better than SCC
Chang, et al.
SEER review, SCC = adeno OS
Bollschweiler 2009
Reproduced with permission
SCC
Adeno
SCC vs. Adenocarcinomas
• Overall outcomes to different therapy modalities
appears similar
• However, different responses to therapy are seen
– SCC better response to localized therapy
– Adenos better survival if response
• Further investigation into these differences is warranted
• Biologic therapies
– Cetuximab
• Benefit in head and neck cancers
• EGFR over-expression seen more in SCC than adeno
• Lordick, rand ph II of chemo +/- cetuximab shows better PFS (5.7
vs. 3.6 mo) and OS (9.5 vs. 5.5 mo) with cetuximab
• EXPAND trial
What about the GE junctional
and cardia tumors?
• Increasing incidence that goes along with distal
esophageal and gastric cardia tumors
• Similar etiologies
• Should we treat distal esophageal adenocarcinomas,
GE junctional tumors, and gastric cardia tumors the
same?
• 2010 TNM staging classifies esophageal
adenocarincomas, GE junctional tumors, and stomach
tumors in proximal 5 cm the same (as esophageal
tumors)
– The cardia stomach tumors are different from the distal
Conclusions
• There are more questions than answers
• The face of esophagogastric cancers is changing
– Alarming increasing incidence of esophageal adenocarcinomas
– We can see potential mechanisms of prevention
• For now we have to continue to base treatment on the available trial
data
– SCC and adeno have same overall outcomes, but behave differently
• Future trials
– Can we limit populations in trials that already have accrual issues?
– Knowing the epidemiology shifts in the West, how to interpret data from
other regions
• Japan – distal gastric cancers more common, SCC still more common
outside Western countries
• Meta-analysis shows different benefits from neoadjuvant CRT vs. surgery
depending on US vs. Europe vs. Asia – histology or other reasons?
– If we can find markers associated with progression to cancer based on
different risk factors, can we find potential new treatment targets?