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Pancreatic Cancer Screening

Pancreatic Cancer Screening. Myth or Manna?. Roberto M. Gamarra, MD, FACG, FACP Director of Endoscopic Ultrasonography Providence Hospital St. John-Providence Health System. Disclosures. None. Introduction to Pancreatic Cancer. Pancreatic Cancer.

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Pancreatic Cancer Screening

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  1. Pancreatic Cancer Screening • Myth or Manna? Roberto M. Gamarra, MD, FACG, FACP Director of Endoscopic Ultrasonography Providence Hospital St. John-Providence Health System

  2. Disclosures • None

  3. Introduction to Pancreatic Cancer

  4. Pancreatic Cancer • 4th leading cause of cancer death but only 10th most common cancer • Estimated new cases in 2013: 45,220 • Estimated number deaths in 2013: 38,460 • % of all new cancer cases: 2.7% • % of all cancer deaths: 6.6% • 1.5% lifetime risk in the general population • 6% survive 5 years SEER Database 2013: http://seer.cancer.gov/statfacts/html/pancreas.html

  5. Pancreatic Cancer Carcinomain situ Minute<10 mm T1 <20 mm Large resectable Unresectable 85% 20-40% 10-20% 5-Year Survival 0-2% Chari, et al. Sem Oncol 2007 Compton CC, Mulvihill SJ. Prognostic factors in pancreatic carcinoma. Surg Oncol Clin N Am 1997; 6:533-54

  6. Pancreatic Cancer: 5-Year Survival Compton CC, Mulvihill SJ. Prognostic factors in pancreatic carcinoma. Surg Oncol Clin N Am 1997; 6:533-54

  7. Paradigm Shift is Needed • No change in incidence or mortality over decades- Unlike breast, colon, and lung! • No major advances in pancreatic cancer treatment- Some modest advances in chemotherapy and surgical techniques- Little impact on survival

  8. Argument Against Screening • Pancreatic cancer is rare (9-12/100K/year) • 90% cases are sporadic • Testing not simple • Testing has potential to cause harm • Testing not cheap • Not proven to reduce mortality!

  9. Argument Against Screening Unclear Cost-Effectiveness • Decision analysis to compare 1-time screening with EUS vs no screening in hypothetical cohort of 100 FPC kindreds • Assumed 20% prevalence and 90% sensitivity of EUS/ERCP- Remained cost-effective for prevalence >16% and sensitivity >84% • Cost-effectiveness of $16,885/life-year saved • Procedure cost had limited effect on cost-effectiveness Rulyak SJ, et al. Cost-effectiveness of pancreatic cancer screening in familial pancreatic cancer kindreds. Gastrointest Endosc 2003; 57:23-9

  10. Yield of Common Screening Tests Debatable Survival Advantage • Pap smear for cervical dysplasia/cancer • Mammogram for breast cancer (~0.76) • PSA for prostate cancer • Occular pressure for glaucoma • Colonoscopy for colon adenoma/cancer (~4%/0.1%)

  11. Why the Renewed Interest in Early Diagnosis • Better understanding of pathogenesis and natural history • Estimated accumulation of mutations in primary lesions- 11.7 years until overt cancer- 6.8 years until overt metastases • Improved resolution of CT and MRI • Development of EUS-FNA to provide cytologic diagnosis • Advances in molecular testing and cytogenetics Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. nature 2010; 467:1114-7

  12. Aberrantcrypt foci Small adenoma Largeadenoma Coloncarcinoma Normal Multistep Carcinogenesis “Cancer is, in essence, a genetic disease” Vogelstein B, et al. Genetic alterations during colorectal-tumor development. NEJM 1988; 319:525-32

  13. Precursor Lesions

  14. Premalignant Lesions • Pancreatic ductal and acinar adenocarcinoma • Pancreatic intraepithelial neoplasia • Mucinous cystic neoplasms • Intraductal papillary mucinous neoplasms (85%) (15%)

  15. Premalignant Lesions

  16. IPMNs • Most common lesion identified in screening populations! • Genetic mutational progression poorly understood • Often mutlifocal • Difficulty in distinguishing which will progress

  17. Mucinous Cystic Neoplasms • Natural history poorly understood • Typically unifocal • >95% in women • Treatment is surgery regardless of size or other risk factors • Difficulty is in distinguishing them from IPMNs preoperatively

  18. PanINs • = Microscopic epithelial lesion located in smaller pancreatic ducts, characterized by cytologic atypia • Most common precursor found in pancreatic cancer!!! • Associated with... ... advanced age, pancreatitis, and invasive cancer • Divided by degree of dysplasia (PanIN-1, -2, and -3) • Management based on dysplasia and patient factors Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res 2000; 6: 2969-2972 Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, Kern SE, Hruban RH. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 2000; 60: 2002-2006 Brune K, Abe T, Canto M, O’Malley L, Klein AP, Maitra A, Volkan Adsay N, Fishman EK, Cameron JL, Yeo CJ, Kern SE, Goggins M, Hruban RH. Multifocal neoplastic precursor lesions associated with lobular atrophy of the pancreas in patients having a strong family history of pancreatic cancer. Am J Surg Pathol 2006; 30: 1067-1076

  19. PanINs

  20. Genomic sequencing studies: 15-years from initiation to metastases! Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. nature 2010; 467:1114-7

  21. Genomic Sequencing and Natural History • May be a large window of opportunity to intervene • Genomic sequencing on cancer cells at autopsy • Differential accumulation of mutations in primary and metastatic lesion, estimated - 11.7 years until overt cancer development- 6.8 years from overt cancer to metastases Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. nature 2010; 467:1114-7

  22. Can PanINs Be Found?

  23. Lobulocentric Atrophy

  24. EUS Detects IPMNs & PanINs

  25. PanIN Lesion

  26. Vague Hypoechoic Region

  27. Who to Screen?

  28. Pancreatic Cancer Risk Factors Low-Risk <5-fold • Male • Black • Ashkenazi Jew • Obesity (1.7-fold) • Heavy alcohol use • Smoking (25%)(2-fold) • Diabetes mellitus (2-fold) • H. pylori infection? • Non-O blood type? Adapted from Brand R, et al. Gut 2007.

  29. Who Should Be Screened? • Only 10% of cases attributable to family history of genetic syndrome • Strong family history: (2 to 32-fold) • 5 genetic syndromes:- Peutz-Jeghers syndrome (PJS)- Familial atypical multiple mole melanoma (FAMMM)- Hereditary pancreatitis- Lynch syndrome (HNPCC)- BRCA2 (3 to 10-fold) (BRCA1?) Wang W, Chen S, Brune KA, Hruban RH, Parmigiani G, Klein AP. PancPRO: risk assessment for individuals with a family history of pancreatic cancer. J Clin Oncol 2007; 25: 1417-1422

  30. Familial Pancreatic Cancer * p <0.005 Brune, et al. JNCI 2010

  31. RR 5-10% RR>10% Risk Factors High-Risk Individuals: 10%

  32. 3 Categories of Risk Lynch syndromeBRCA1

  33. Tests

  34. Characteristics of Good Screening Tests Accurate Available Safe Reproducible Cost-Effective

  35. Not Ready for Prime-Time! Genetic & Serologic Markers • Serum, stool, or pancreatic tissue • Genetic markers: - p53, K-ras, p16 (INK 4a) promoter methylation, macrophage inhibitor cytokine-1 (MIC-1), microRNAs • Serologic markers:- CA 19-9 (sensitivity 79% and specificity of 82%), CEACAM1, osteopontin, matrix metallopeptidase 7, adenosine deaminase, mucin 1, tumor-M2-pyruvate kinase and oncofetal antigens, SPan-1, DUPAN-2, Alpha4GnT, PAM4

  36. EUS for Pancreatic Cancer • EUS & MDCT in 104 patients (90 had pancreatic cancer) • EUS sensitivity 98% • CT sensitivity 86% • EUS was superior to CT for tumor detection and T-staging and similar to CT for N-staging • Sensitivity in screening setting is less clear DeWitt, et al. 2005 Ann Int med

  37. EUS Current Diagnostic Test of Choice • Superior sensitivity and specificity (studies done looking only at academic centers) • Most cost-effective Compiled by Chen, et al. Am J Gastro 2004

  38. CAPS 3 Study Canto M, et al. Frequent detection of pancreatic lesions in asymptomatic high-risk individuals. Gastorenterol 2012; 142:796-804

  39. The Data

  40. Initial Clinical Studies • 12 published screening studies limited to high-risk populations • All but 1 study used EUS as initial test of choice- Trend has been to avoid or not utilize ERCP • EUS has highest sensitivity in detecting pancreatic lesions • Screening is safe • Most clinically important lesions found on index test • Limitation: many benign lesions with malignant potential that require work-up

  41. Clinical Studies Brentnall TA, et al. Ann Intern Med. 1999; 131:1247-255. Canto MI, et al. Clin Gastroenterol Hepatol 2004; 2:606-21. Canto MI, et al. Clin Gastroenterol Hepatol 2006; 4:766-81, quiz 665. Poley JW, et al. Am J Gastroenterol 2009; 104:2175-81. Langer P, et al. Gut 2009; 58:1410-18. Verna EC, et al. Clin Cancer Res. 2010; 16:5028-37. Ludwig E, et al. Am J Gastroenterol. 2011; 106:946-54

  42. CAPS 2 Study • 78 patients: 6 PJS and 72 familial pancreatic cancer history vs. 149 controls • EUS & CT +/- ERCP • 10% yield for premalignant lesions (higher than mammograms) • 3 extra-pancreatic cancers found • 1 patient refused surgery & developed metastatic CA • Proof: premalignant lesions can be found! • Proof: at risk individuals can be identified! Canto MI, et al. Screening for early pancreatic neoplasia in high risk individuals: a prospective controlled study. Clin Gastroenterol Hepatol 2006; 4:766-81

  43. Consensus Conference 50 experts from 10 different countries • When to start screening? 40 or 10 years prior to relative with cancer? • How to screen? EUS and MRI/MRCP? • How often to follow? Yearly? • When to resect? • How much to resect? • Does it make an impact on survival? Canto MI, Harinck F, Hruban RH, et al. International cancer of the pancreas screening (CAPS) consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013; 62:339-47

  44. Screening Consensus Who Should Be Screened? Canto MI, Harinck F, Hruban RH, et al. International cancer of the pancreas screening (CAPS) consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013; 62:339-47

  45. Screening Consensus How Should Screening Be Performed? Canto MI, Harinck F, Hruban RH, et al. International cancer of the pancreas screening (CAPS) consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013; 62:339-47

  46. Screening Consensus When Should Surgery Be Offered? • Most lesions found during screening are BD-IPMNs • Sendai consensus guidelines • Resection recommended:- Symptoms attributable to the cyst- >3 cm- Cyst contains mural nodules • Majority agreed that surgery should be considered for suspected BD-IPMNs in HRIs which are >2 cm Canto MI, Harinck F, Hruban RH, et al. International cancer of the pancreas screening (CAPS) consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013; 62:339-47 Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatol 2006; 6:17-32

  47. Screening Consensus When Should Surgery Be Offered? Canto MI, Harinck F, Hruban RH, et al. International cancer of the pancreas screening (CAPS) consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013; 62:339-47

  48. Screening Consensus What is Considered Successful Screening? Canto MI, Harinck F, Hruban RH, et al. International cancer of the pancreas screening (CAPS) consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013; 62:339-47

  49. Conclusion

  50. What to Tell Patients • No recommendations for screening asymptomatic patients in the general population • Patients in high risk groups have an option of considering EUS and MRI/MRCP • Should be done in centers that have a program in place

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