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Pancreatic Cancer Review

Pancreatic Cancer Review. Gina Vaccaro , MD May 20, 2009. Outline. Anatomy Histologic types Epidemiology Precursor lesions Presentation Treatment. Anatomy of the pancreas. DePinho, Nature Reviews, 2002. Anatomy of the pancreas. DePinho, Nature Reviews, 2002. Histology.

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Pancreatic Cancer Review

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  1. Pancreatic CancerReview Gina Vaccaro, MD May 20, 2009

  2. Outline • Anatomy • Histologic types • Epidemiology • Precursor lesions • Presentation • Treatment

  3. Anatomy of the pancreas DePinho, Nature Reviews, 2002

  4. Anatomy of the pancreas DePinho, Nature Reviews, 2002

  5. Histology • Ductaladenocarcinoma, PDAC (>85%) • Acinar cell carcinoma • Pancreatic Neuroendocrine Tumor • Cystic neoplasms • Other- Lymphoma (NHL)

  6. DePinho, Nature Reviews, 2002

  7. DePinho, Nature Reviews, 2002

  8. DuctalAdenocarcinoma by the Numbers • 33,730 cases/yr in US • 30,000 deaths/yr • 7th- 8th decade of life- peak incidence • 72 years- median age at diagnosis • 4th- most common cause of Ca-related death in US • 15-20%- 5 yr survival if resectable • 3%- 5 yr survival, all stages

  9. 2007 Estimated US Cancer Cases* Men766,860 Women678,060 26% Breast 15% Lung & bronchus 11% Colon & rectum 6% Uterine corpus 4% Non-Hodgkin lymphoma 4% Melanoma of skin 4% Thyroid 3% Ovary 3% Kidney 3% Leukemia 21% All Other Sites Prostate 29% Lung & bronchus 15% Colon & rectum 10% Urinary bladder 7% Non-Hodgkin 4% lymphoma Melanoma of skin 4% Kidney 4% Leukemia 3% Oral cavity 3% Pancreas 2% All Other Sites 19% *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2007.

  10. 2007 Estimated US Cancer Deaths* Men289,550 Women270,100 Lung & bronchus 31% Prostate 9% Colon & rectum 9% Pancreas 6% Leukemia 4% Liver & intrahepatic 4%bile duct Esophagus 4% Urinary bladder 3% Non-Hodgkin 3% lymphoma Kidney 3% All other sites 24% 26% Lung & bronchus 15% Breast 10% Colon & rectum 6% Pancreas 6% Ovary 4% Leukemia 3% Non-Hodgkin lymphoma 3% Uterine corpus 2% Brain/ONS 2% Liver & intrahepatic bile duct 23% All other sites ONS=Other nervous system. Source: American Cancer Society, 2007.

  11. Predisposing Factors • Age • Smoking • Chronic pancreatitis • Obesity • Diabetes mellitus • None?

  12. Familial Syndromes • Hereditary Breast and Ovarian cancer (BRCA2) • Peutz-Jeghers (LKB1) • Familial atypical multiple mole melanoma (p16INK4a) • Lynch syndrome (MSH2, MLH1, etc.) • Hereditary pancreatitis (PRSSI)

  13. Familial Syndromes • Account for < 20% of the familial aggregation of PC • National Familial Pancreas Tumor Registry (Hopkins)- 1200 families • Familial PC- at least two 1st degree relatives Risk is 18X baseline • Second degree relatives in familial PC kindreds have increased risk (3.7% vs. 0.6%)

  14. Precursor Lesions • PanIN (Pancreatic intraepithelial neoplasia) • MCN (Mucinous cystic neoplasm) • IPMN (Intraductal papillary mucinous neoplasm)

  15. Genetic Progression Model DePinho, Nature Reviews, 2002

  16. Regeneration  Tumorigenesis DePinho, Nature Reviews, 2002

  17. KRAS mutation is necessary, but not sufficient • Activating mutations are the 1st known genetic alterations • Occur sporadically in normal pancreatic tissue • Detected in ~30% of early neoplasms • Nearly 100% of advanced PDAC • Mice with pancreas-specific KRASG12Ddevelop PanIN, can progress to PDAC in the appropriate tumor suppressor background.

  18. A Target Rich Environment DePinho, Gen Dev, 2006

  19. Presentation • Abdominal pain (Bad sign) • Jaundice (Head lesions) • Weight loss • New onset diabetes mellitus • Pancreatic enzyme insufficiency (diarrhea, floating/fatty stools)

  20. Diagnosis • FNA of the primary mass or distant metastases • FNA of the primary is obtainable with EUS (endoscopic ultrasound) • EUS is also useful for staging, invasion into surrounding vessels (SMA, SMV) • Determination of resectability

  21. Case 1 • 66 yo female presented with upper abdominal pain • Non-smoker, father has pancreatic cancer • Started on PPI by PCP • Pain continued, developed anorexia, 8 lb weight loss • U/S- intra and extra hepatic biliaryductaldilitation • CT- 1.4cm pancreatic head mass, 18mm CBD, dilated pancreatic duct

  22. Case 1 • EUS- 2 x 1.8cm pancreatic head mass, 18 mm CBD, no nodes • FNA- adenocarcinoma • Staged T3N0 • No involvement of critical vascular structures. • Underwent “Whipple” resection

  23. Case 1 • Pathology: 2.5 cm ductaladenocarcinoma T4N1 (1/19 nodes) Positive SMA and radial margin Angiolymphatic and perineural invasion Poor prognosis- 5 yr survival 10-20% Recommendation- Adjuvant chemotherapy, chemoradiation (6 months)

  24. Case 2 • 62 yo male presented with L flank • Presented to urgent care, MD palpated an abdominal mass • CT done- 11 x 8 cm mass in the body of the pancreas, no mets, obliteraion of portal, splenic, SMV • Also noted to have L renal stone • Patient has no symptoms, no weight loss, no pain

  25. Case 2

  26. Case 2 • EUS/FNA- low grade neuroendocrine neoplasm • Disease is not resectable • Prognosis is good, median survival >5yrs • Options: Observation Somatostin analog Chemotherapy Biologic therapy

  27. Extent of disease at presentation Localized/Resectable (15-20 %) MS 15-19 mo Locally Advanced/Unresectable (40 %) MS 8-12 mo Metastatic (40 %) MS 3-6 mo

  28. Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ (also PanIN 3) T1 Tumor limited to pancreas, <=2cm T2 Tumor limited to pancreas, >2cm T3 Tumor extends beyond pancreas w/o involvement of celiac axis or SMA T4 Tumor invades celiac axis or SMA (unresectable) Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Regional lymph node metastases Distant Metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Staging (AJCC 2002) Stage Grouping Stage 0 Tis N0 M0 Stage IA T1 N0 M0 Stage IB T2 N0 M0 Stage IIA T3 N0 M0 Stage IIB T1 N1 M0 T2 N1 M0 T3 N1 M0 Stage III T4 Any N M0 Stage IV Any T Any N M1

  29. Five-year Relative Survival (%)* during Three Time Periods By Cancer Site 1984-1986 1996-2002 Site 1975-1977 • All sites 50 53 66 • Breast (female) 75 79 89 • Colon 51 59 65 • Leukemia 35 42 49 • Lung and bronchus 13 13 16 • Melanoma 82 86 92 • Non-Hodgkin lymphoma 48 53 63 • Ovary 37 40 45 • Pancreas 2 3 5 • Prostate 69 76 100 • Rectum 49 57 66 • Urinary bladder 73 78 82 † *5-year relative survival rates based on follow up of patients through 2003. †Recent changes in classification of ovarian cancer have affected 1996-2002 survival rates. Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control and Population Sciences, National Cancer Institute, 2006.

  30. Why is pancreatic cancer so hard to treat?

  31. Factors to Overcome • No adequate screening test • High incidence of metastatic disease at presentation • Fulminant clinical course • Lack of adequate systemic therapies • Chemotherapy resistant • Radiation resistant • Lack of understanding of the biology

  32. Resectable Disease

  33. Criteria for Unresectability • Determined by multi-disciplinary evaluation • Extrapancreatic involvement • (extensive peripancreatic nodal involvement and/or distant mets) • Encasement or occlusion of the SMV or SMV-portal vein confluence • (SMV reconstruction may be feasible) • Direct involvement of SMA, IVC, aorta, celiac axis

  34. Pancreaticoduodenectomy (Whipple) Operative mortality <2-3% in major surgical centers Surgery (tumors of head, neck or uncinate process)

  35. Often present late with larger tumors and frequent metastases Distal pancreatectomy +/- splenectomy Surgery (tumors of body or tail)

  36. Chemotherapy

  37. 5-fluorouracil • Pyrimidine analog • In use for over 40 yrs • Thymidylatesynthase inhibitor • Pancreatic, colon, breast, esophageal, gastic cancer, etc.

  38. Gemcitabine • Nucleoside analog • Difluorinated analog of deoxycytidine • Pancreas, breast, lung and ovarian

  39. Adjuvant Therapy

  40. Adjuvant therapy • Rationale: High risk of local and systemic recurrence Overall poor prognosis • 5-yr survival after resection: 25-30% node-neg vs. 10% node-pos • Current standard: No universally accepted standard approach

  41. Adjuvant therapy • 5 major randomized trials • GITSG, EORTC, ESPAC-1, RTOG 9704, CONKO-1 • Over 1200 patients studied • Significant methodological differences • Chemoradiotherapy in N. America (GITSG, RTOG) • Chemotherapy alone in Europe (EORTC,ESPAC-1, CONKO)

  42. Trial RT dose Chemo MS (Mo) 1 yr % 2 yr % 5-fu based chemoradiation GITSG 40 Gy(split) Bolus 5fu 20 (p=.01) 63 42 None None 11 49 15 EORTC 40 GY(split) CI 5-fu17.1 (p=.099) 65 37 None None 12.6 40 23 ESPAC-1 2x2 factorial design

  43. ESPAC-1 (5-fu) Chemoradiotherapy vs. none MS 15.9 vs. 17.9 mos 2-yr survival 29 vs. 41 % 5-yr survival 10 vs. 20 % Chemotherapy vs. none MS20.1 vs. 15.5 mos 2-yr survival 40 vs. 30 % 5-yr survival 21 vs. 8 % Neoptolemos, NEJM 2004

  44. Kaplan-Meier estimates of survival according to whether or not patients Received chemoradiotherapy (Panel A) or chemotherapy (Panel B) Neoptolemos, NEJM 2004

  45. ESPAC-1 Limitations • Trial design (2 x 2 factorial) • Possible selection bias • Suboptimal radiation dose • Only 70% received 40 Gy • Uses 5-fu based chemotherapy • Design delays initiation of adjuvant chemotherapy in the combination arm

  46. Gemcitabine-based adjuvant therapy • RTOG 9704 (ASCO 2006) 442 subjects All received chemoradiation (50.4 Gy) + CI 5-fu 2 Arms: Additional 5-fu Additional Gemcitabine No overall difference in aggregate survival Head lesions only Gemcitabine arm superior MS 20 vs. 17 mos 3-yr OS 32 vs. 21 % (p=0.047)

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