1. Understanding the evolution in the epidemiology of esophagogastric cancers Johanna Bendell, MD Director, GI Oncology Research Sarah Cannon Research Institute

2. 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:

3. 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 –7 th 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

4. Annual Prevalence of Esophageal Cancer Pisani, 2001

5. 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

6. 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 2008 Reproduced with permission

7. Distribution of esophageal cancer by segment

8. 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) Takezaki 2000, Wu 2001, Brown 2001, Kamangar 2009

9. 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 BMI, Quartile Chow 1998, Abnet 2008, Corley 2008+2007, Edelstein 2007

10. 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

11. 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

12. Gastric Cancer Incidence U.S. 2009 –21,130 new cases, 10,620 deaths –10 cases per 100,000 –50% fatality rate Worldwide –3 th 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

13. 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

14. 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 2002 Reproduced with permission

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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?

21. 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

22. 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

23. 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

24. Chemoradiation plus surgery SCC Adeno Bollschweiler 2009 Reproduced 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

25. 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

26. 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

27. 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?