Understanding the evolution in the epidemiology of esophagogastric cancersJohanna Bendell, MDDirector, GI Oncology ResearchSarah Cannon Research Institute

Learning Objectives

• 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

After reading and reviewing this material, the participant should be better able to:

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

0 1 2 3 4 5 6 7 8 9

China, Korea, Mongolia

Japan

Western Europe

South-Central Asia

North America

Sub-Saharan Africa

Eastern Europe

Oceania

Latin America and Carribbean

South-Eastern Asia

Middle East and Northern Africa

Cases / 100,000

WomenMen

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, 1975-2004

• 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

Brown, et al. JNCI 2008Reproduced with permission

Distribution of esophageal cancer by segment

Segment SCCMale

SCCFemale

ADCMale

ADCFemale

UpperThird

19% 20% 2% 4%

MiddleThird

40% 47% 13% 18%

LowerThird

35% 28% 80% 73%

Over-lapping

6% 6% 5% 5%

What happened???• “Traditional” risk

factors for esophageal cancers

• Tobacco and EtOH– 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)

0

2

4

6

8

10

12

14

16

18

0 20-29 30-39 40 + 0 3.5 11 14.5 25 28.5 36+

AdenocarcinomaSquamous Cell CarcinomaAdenocarcinomaSquamous Cell Carcinoma

Cigarettes per Day Drinks per Week

0

1

2

3

4

5

6

Years Since Quitting

Odds Ratio

Quitting Smoking and Esophageal Cancer

Data from Wu, 2001 and Castellsague, 2000

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

0

0.5

1

1.5

2

2.5

3

I (low) II III IV

Squamous Cell

Adenocarcinoma

BMI, Quartile

Chow 1998, Abnet 2008, Corley 2008+2007, Edelstein 2007

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 cancer? • Rates of gastric

cancer are actually declining– Worldwide effect

El-Serag, et al. Gut 2002

Reproduced with permission

Rates of esophageal and gastric cancers in the U. S.

• For gastric cancer, over time incidence is stable across all groups– Race– Gender

El-Serag, et al. Gut 2002Reproduced with permission

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 meta-analyses

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

SCC

AdenoBollschweiler 2009Reproduced with permission

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

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?