1. Early diagnosis of pancreatic cancer Moderators: Banke Agarwal, MD David Linehan, MD Panelists: Suresh Chari, MD Michael Goggins, MD David Whitcombe, MD Maurits Weirsema, MD

2. Why is early diagnosis desirable Despite considerable investment in improving therapy, the outcomes in pancreatic cancer have not changed much in past several decades Despite considerable investment in improving therapy, the outcomes in pancreatic cancer have not changed much in past several decades Approximately 85% of patients have Stage IV disease at the time of initial presentation Approximately 85% of patients have Stage IV disease at the time of initial presentation Baxter et al, Ann Surg Oncol 2007

3. Why is early diagnosis desirable? Baxter et al, SEER database

4. The outcomes in patients with smaller tumors are consistently better than those with larger tumors in several published studies The outcomes in patients with smaller tumors are consistently better than those with larger tumors in several published studies

5. Agarwal et al Pancreas 2008 Survival and resectability in patients with pancreatic cancer based on tumor size Washington University Pancreas Cancer Database 2000-2007 (unpublished) N=540

6. Size of pancreatic tumor at diagnosis over past few decades First author Year of publication Patient accrual Institution Mean tumor size Fortner19961979-1991MSKCC 3.9 cm Yeo19951970-1994JHMI 3.0 cm Nitecki19951981-1991Mayo 3.1 cm Sohn20011984-1999JHMI 3.2 cm Schmidt20041980-2002IUPUI Agarwal20042000-2002MDACC 3.0 cm

7. Why are we not diagnosing early cancers despite improvements in imaging? Patients with early cancers are usually asymptomatic and do not present for medical attention Patients with early cancers are usually asymptomatic and do not present for medical attention Early cancers noted in asymptomatic patients are often overlooked by radiologists Early cancers noted in asymptomatic patients are often overlooked by radiologists

8. Gangi et al AJR 2004

9. Why renewed emphasis on early diagnosis now? –Improved resolution with CT/MRI –Advent of EUS-FNA to provide cytologic diagnosis in patients with early stage pancreatic cancers –Advances in molecular testing –Better understanding of pathogenesis and natural history of pancreatic cancer –Less nihilism?

10. Attempts at early diagnosis of pancreatic cancer pancreatic cancer screening = ??? Is there an identifiable prodrome? Can we identify an at-risk population?

11. Characteristics of diseases amenable to screening 1. Substantial morbidity or mortality if untreated 2. High clinical prevalence –High risk populations 3. Existence of critical point and appropriate therapy 4. Low incidence of pseudo-disease

12. What speaks against screening? Harm due to screening Harm due to screening –Complications –Overtreatment Low yield/cost Low yield/cost No proof that stage migration results in improved outcome No proof that stage migration results in improved outcome

13. Q. Is there a good case for screening pancreatic cancer  In general population?  Incidence is 1 in 100,000  In high risk patient groups?

14. Prevalence of cancers that are currently screened Colon cancer - Colon cancer - Breast cancer - Breast cancer - Lung cancer ? - Lung cancer ? - Cervical cancer - Cervical cancer - Prostate cancer - Prostate cancer -

15. Characteristics of screening test 1. Test accuracy 2. Test reproducibility 3. Test safety, availability and cost effectiveness

16. Which tests are best potential candidates for pancreatic cancer screening 1. Serum markers 2. Cross sectional imaging with spiral CT or MRI 3. EUS/FNA 4. ERCP 5. Abdominal US 6. None of the above

17. Potential strategies for diagnosing pancreatic cancer in early stages Identification of high risk groups for screening Identification of high risk groups for screening Screening/surveillance of patients with familial or environmental predisposition Screening/surveillance of patients with familial or environmental predisposition Development of molecular biomarkers for screening or identifying high risk population Development of molecular biomarkers for screening or identifying high risk population

18. Enriched populations for screening for pancreatic cancer Suresh Chari- 10 min Are there any enriched population subsets with higher prevalence of pancreatic cancer? Are there any enriched population subsets with higher prevalence of pancreatic cancer? –New onset diabetes mellitus –Idiopathic acute pancreatitis in the elderly –New diagnosis of chronic pancreatitis –New onset unipolar depression in the elderly What percentage of pancreatic cancers have associated above presentations? What percentage of pancreatic cancers have associated above presentations? What percentage of patients with above presentations have pancreatic cancer? What percentage of patients with above presentations have pancreatic cancer? Can we further enrich above populations based on: Can we further enrich above populations based on: –Age, h/o smoking –Further defining the clinical syndrome –Use of serum markers

19. Familial pancreatic cancers David Whitcomb 10 mins What proportion of pancreatic cancers are familial? What proportion of pancreatic cancers are familial? What is the risk of pancreatic cancer in various familial conditions? What is the risk of pancreatic cancer in various familial conditions? What are the familial conditions where surveillance for pancreatic cancer would seem justified? What are the familial conditions where surveillance for pancreatic cancer would seem justified? What are the currently available means for evaluating these patients for pancreatic cancer and how effective are they? What are the currently available means for evaluating these patients for pancreatic cancer and how effective are they? Will lessons learned in familial cancers apply to sporadic ones? Will lessons learned in familial cancers apply to sporadic ones?

20. Molecular markers to aid in early diagnosis of pancreatic cancer Michael Goggins 10 mins What will be the required performance characteristics of a serum molecular marker to be What will be the required performance characteristics of a serum molecular marker to be –Useful in screening of pancreatic cancer –Diagnosis of pancreatic cancer –Prognostication Are there any molecular markers in the horizon that can potentially be used for above purposes? Are there any molecular markers in the horizon that can potentially be used for above purposes? What is the current state of the art in development of biomarkers for pancreatic cancer? What is the current state of the art in development of biomarkers for pancreatic cancer? Is there a precursor in pancreatic cancer carcinogenesis (analogous to HGD e.g.,PanIN3) that can be reliably diagnosed pre-operatively. Is there a precursor in pancreatic cancer carcinogenesis (analogous to HGD e.g.,PanIN3) that can be reliably diagnosed pre-operatively.

21. How can EUS/FNA help in early diagnosis of pancreatic cancer Maurits Wiersema 10 mins What are the performance characteristics of EUS-FNA for identifying and diagnosing early tumors? What are the performance characteristics of EUS-FNA for identifying and diagnosing early tumors? How does EUS/FNA compare with CT or MRI for diagnosis of early cancers? How does EUS/FNA compare with CT or MRI for diagnosis of early cancers? What is the risk of complications with EUS and EUS-FNA? What is the risk of complications with EUS and EUS-FNA? Can EUS potentially be used for detecting and diagnosing pancreatic cancer in enriched population subsets? Can EUS potentially be used for detecting and diagnosing pancreatic cancer in enriched population subsets? Role of EUS in diagnosing cancer in patients with subtle/non- specific findings suggestive of cancer on CT scan/MRI? Role of EUS in diagnosing cancer in patients with subtle/non- specific findings suggestive of cancer on CT scan/MRI? Are there workforce issues if screening became generally accepted? Are there workforce issues if screening became generally accepted? Is there a realistic mechanism for quality control? Is there a realistic mechanism for quality control?

22. What are the performance characteristics of EUS-FNA for identifying and diagnosing early tumors? EUS is more sensitive than MDCT for tumor detection (98% vs 86%) with a more marked difference in smaller tumors – DeWitt 2004 Ann Intern Med EUS is more sensitive than MDCT for tumor detection (98% vs 86%) with a more marked difference in smaller tumors – DeWitt 2004 Ann Intern Med Operating characteristics for EUS in precursor lesions is unknown – Canto 2006 CGH, Kimmey 2002 GIE Operating characteristics for EUS in precursor lesions is unknown – Canto 2006 CGH, Kimmey 2002 GIE –PanIN equivalents – are changes of chronic pancreatitis a surrogate? –IPMN –< 1 cm masses

23. What are the performance characteristics of EUS-FNA for identifying and diagnosing early tumors? 72% of high risk patients have features of chronic pancreatitis vs 14% of controls 72% of high risk patients have features of chronic pancreatitis vs 14% of controls 25% of patients in high risk kindreds will have a ‘neoplastic’ abnormality on initial or short term follow up 25% of patients in high risk kindreds will have a ‘neoplastic’ abnormality on initial or short term follow up The estimated cumulative frequency of pancreatic cancer in this group is 5-40% The estimated cumulative frequency of pancreatic cancer in this group is 5-40% EUS is sensitive but specificity is problematic EUS is sensitive but specificity is problematic Canto CGH 2004 and 2006, Levy CGH 2006

24. How does EUS/FNA compare with CT or MRI for diagnosis of early cancers? EUS FNA of Pancreas Masses When CT FNA or ERCP Sampling are Negative Gress et al, Annals of Internal Medicine 2001

25. How does EUS/FNA compare with CT or MRI for diagnosis of early cancers? Diagnostic yield in enriched screening cohort Diagnostic yield in enriched screening cohort –EUS 7 of 8 –CT 5 of 8 –ERCP 2 of 8 EUS FNA can show mucinous material and dysplasia which may be helpful EUS FNA can show mucinous material and dysplasia which may be helpful Canto CGH 2004 and 2006, Levy CGH 2006

26. What is the risk of complications with EUS and EUS-FNA? EUS similar to EGD EUS similar to EGD 1-2% incidence of pancreatitis with FNA 1-2% incidence of pancreatitis with FNA

27. Post EUS FNA Pancreatitis/Duct Leak

30. Can EUS potentially be used for detecting and diagnosing pancreatic cancer in enriched population subsets? Yes Yes –IPMN is a common precursor –Subtle abnormalities may not be uniformly recognized (hypoechoic foci, inhomogeneity) –Specificity issues remain

31. Role of EUS in diagnosing cancer in patients with subtle/non-specific findings suggestive of cancer on CT scan/MRI? Fletcher 2003 Radiology Tumor Detection in Patients with Suspected Pancreas Cancer

32. Summary Are there workforce issues if screening became generally accepted? Are there workforce issues if screening became generally accepted? –No reimbursement –Probably the most difficult EUS exam to perform Is there a realistic mechanism for quality control? Is there a realistic mechanism for quality control? –US interobserver agreement varies depending on severity of abnormality –Readily available gold standard is available

33. Questions to panel What is the current status of pancreas cancer screening or early diagnosis today? What is the current status of pancreas cancer screening or early diagnosis today? –Who should be screened? How much should the population be enriched before testing for pancreatic cancer becomes justifiable? How much should the population be enriched before testing for pancreatic cancer becomes justifiable? –How often? What age should we start/stop? –What modality?

34. Questions to panel What is the future of pancreas cancer screening or early diagnosis? What is the future of pancreas cancer screening or early diagnosis? –EUS –Biomarkers Where should we look (serum, plasma, pancreatic fluid, urine)? Where should we look (serum, plasma, pancreatic fluid, urine)? –Functional or molecular imaging Can we “see” PanIns? Can we “see” PanIns?

35. Questions to panel Will stage migration/early detection lead to better outcomes? Will stage migration/early detection lead to better outcomes? What are the impediments to screening and how do we overcome them? What are the impediments to screening and how do we overcome them? Is there a role for prophylactic pancreatectomy? Is there a role for prophylactic pancreatectomy?