Faculty Caio Max S. Rocha Lima, MD Professor of Medicine Co-Leader, Colorectal, Pancreatic, Liver, and Related Cancers Group Co-Director, Phase I Unit University of Miami Leonard M. Miller School of Medicine Sylvester Comprehensive Cancer Center Miami, FL Activity Planners Shari J. Dermer, PhD Manager, Educational Strategy and Content Med-IQ Baltimore, MD Lisa R. Rinehart, MS, ELS Director, Editorial Services Med-IQ Baltimore, MD Pancreatic Cancer: Statistics • 45,220 new cases estimated in 2013 • 38,460 deaths from pancreatic cancer estimated in 2013 • > 50% of cases are metastatic at diagnosis 6.0% 5-year survival rate from 2003 to 2009 Number per 100,000 Persons 15 — Localized (9%) 10 — Confined to primary site New Cases Deaths Regional (27%) Spread to regional lymph nodes 5— Distant (53%) 0 —| 1992 Cancer has metastasized | 1995 | 2000 | 2005 Time From Induction, months | 2010 Unknown (11%) Unstaged www.SEER.cancer.gov. Oncogenes • KRAS mutations1 – Very common (> 90%), usually restricted to codon 12 – Early genetic event in pancreatic carcinogenesis and are considered to be a “signature” of pancreatic cancer • BRAF mutations2 – Observed in 30% of the pancreatic cancers with WT KRAS gene • AKT1 gene, AKT2 gene, and MYB gene amplification – Observed in 60%, 10% to 15%, and 10% of pancreatic cancers, respectively3-5 1. Almoguera C, et al. Cell. 1988;53:549-54; 2. Kanda M, et al. Gastroenterology. 2012;142:730-3; 3. Li D, et al. Lancet. 2004;363:1049-57; 4. Cheng JQ, et al. Proc Natl Acad Sci USA. 1996;93:3636-41; 5. Wallrapp C, et al. Cancer Res. 1997;57:3135-9. Tumor Suppressor Genes • Inactivation of the p16 gene1 – Observed in 80% to 95% of sporadic pancreatic cancers • The combination of p16 and KRAS mutations is uncommon in other human tumors and is considered to be a molecular “signature” for pancreatic cancer • Observed at a later stage in pancreatic carcinogenesis than KRAS mutations • p53 gene inactivation2 – Observed in 55% to 75% of cases and is a late event in tumorigenesis • p21 gene inactivation – Early event in the development of pancreatic carcinoma 1. Schutte M, et al. Cancer Res. 1997;57:3126-30. 2. Li D, et al. Lancet. 2004;363:1049-57. Tumor Suppressor Genes • SMAD4 gene1 – Plays a critical role in signaling through the TGF-beta pathway and occurs in about 55% • BRCA2 (her-2/neu)2 – Gene mutation carriers have a 10-fold increased risk of developing pancreatic cancer – Prognostic and may play a role in adjuvant, neoadjuvant, and chemoXRT approaches 1. Ghaneh P, et al. Gut. 2007;56:1134-52. 2. Bachet JB et al. Ann Oncol. 2012; 23: 2327-35. Molecular Features and Risk of Relapse • SMAD4 – Poor prognosis1,2 – Pattern of relapse3,4 • • • • CXCR45 Notch/hedgehog6 Stromal SPARC7-9 Cancer stem cells6 1. Kojima K, et al. Cancer Res. 2007;67:8121-30; 2. Blackford A, et al. Clin Cancer Res. 2009:15:4674-79; 3. Iacobuzio-Donahue CA, et al. J Clin Oncol. 2009;27:1806-13; 4. Crane CH, et al. J Clin Oncol. 2011;29:3037-43; 5. Bachet JB, et al. Ann Oncol. 2012;23:2327-35; 6. Hezel AF, et al. Genes Devel. 2006;20:1216-49; 7. Infante JR, et al. J Clin Oncol. 2007;20:319-25; 8. Neuzillet C, et al. Cancer Metastasis Rev. 2013;32:585-602; 9. Sinn M, et al. J Surg Oncol. 2013;108:398-402. NCCN Definitions: Locally Advanced and Borderline Resectable • Locally advanced – SMA encasement > 180 degrees – Unreconstructable SMV/portal vein occlusion – Any celiac abutment (head) or celiac encasement > 180 degrees (body/tail) – Aortic invasion or encasement – Lymph node metastases beyond field of resection • Borderline resectable – SMA encasement < 180 degrees – SMV/portal impingement – Short-segment SMV occlusion – Celiac encasement < 180 degrees (tail) – Abutment/encasement of hepatic artery NCCN Guidelines. Pancreatic Adenocarcinoma V1.2013; Varadhachary GR. J Gastrointest Oncol 2011;2:136-42. Chemo Alone vs. Chemo-RT Chemo No. of Patients Median Survival (Mos) 1-Year Survival (%) 40 5-FU 5-FU 47 44 8.3 8.2 28 31 GITSG 92832 54 5-FU & SMF* SMF* 22 21 9.7 7.4 41 19 FFCD-SSRO3 60 5-FU & Cis* Gemcitabine 59 60 8.6 13 32 53 ECOG 42014 50.4 Gemcitabine Gemcitabine 34 37 11.0 9.2 50 32 Study Radiation (Gy) ECOG1 *Investigational 1. Klaassen DJ, et al. J Clin Oncol. 1985;3:373-8; 2. GITSG. J Natl Cancer Inst. 1988;80:751-5; 3. Chauffert B, et al. Ann Oncol. 2008;19:1592-9; 4. Loehrer PJ, et al. J Clin Oncol. 2011;29:4105-12. FOLFIRINOX* Experience in LAPC Age Sex Median (range) n (%) 57.5 (41-73) Male Female 10 (56%) 8 (44%) 0 1 8 (44%) 10 (56%) Head Uncinate process Body Tail 11 (61%) 3 (17%) 2 (11%) 2 (11%) Yes No 9 (50%) 9 (50%) SMA encased HA encased Celiac trunk encased Confluence of PV, SV and SMV encaed SMV encaed SV encased 3 (17%) 2 (11%) 3 (17%) ECOG Performance Status Pancreatic tumor location Biliary stent Basis for unresectability *Investigational use. 5( 28%) 4 (22%) 1 (6%) Hosein P, et al. BMC Cancer. 2012;12:199. A FOLFIRINOX* Outcomes in LAPC B 14 patients FOLFIRINOX (3-12 cycles) 1 progressed after 3 cycles 4 patients FOLFIRINOX (6-17 cycles) 4 resectable by imaging 2 R0 resections 1 R1 resection 1 unresectable at E-lap 9 unresectable at maximum response or tolerability Combined chemoradiation (2 ongoing) 3 post-op combined chemoradiation 1 post-op observation 3 resectable by imaging 3 R0 resections 4 still unresectable Patient flowchart for patients assessed as having unresectable disease (panel A, n = 14), and for those assessed as having borderline resectable disease (panel B). 3 resectable by imaging 3 R0 resections 1 unresectable at maximum response or tolerability 3 post-op combined chemoradiation Combined chemoradiation 1 still unresectable *Investigational use. Hosein P, et al. BMC Cancer. 2012;12:199. LAPC: Conclusions • XRT + chemotherapy better then XRT alone • Gemcitabine + XRT is potentially superior to gemcitabine alone – The ECOG study had poor accrual and closed early • Retrospective data: chemo followed by chemoXRT superior to chemoXRT upfront – The role of XRT in LAPC is questioned due to the results of the LAP 07 study • Gemcitabine may be a superior radiosensitizer to 5-FU • The role of FOLFIRINOX in the neoadjuvant setting is emerging International Phase 3 Trial Pancreatic cancer (metastatic) Gemcitabine 1,000 mg/m2 IV weekly x 7 of 8 Gemcitabine 1,000 mg/m2 + Nab-paclitaxel 125 mg/m2 weekly x 3 of 4 Von Hoff DD, et al. N Engl J Med.2013;369:1691-703. Phase 3 Trial: Gemcitabine and Nab-Paclitaxel Nab-Pac Gemcitabine n = 431 Gemcitabine n = 430 HR P value OS, median 8.5 (7.89-9.53) 6.7 (6.01-7.23) 0.72 (0.617-0.835) 0.000015 1-year OS % 35 22 - 0.0002 PFS median 5.5 (4.47-5.95) 3.7 (3.61-4.04) 0.69 (0.581-0.821) 0.000024 23 7 - Outcome RR % Von Hoff DD, et al. GI Cancers Symposium 2013[Abstract LBA148]. PRODIGE 4—ACCORD 11 Trial Design Metastatic pancreatic cancer R A N D O M I Z E For both arms: FOLFIRINOX* Gemcitabine CT scans: obtained every 2 months 6 months of chemotherapy recommended Stratification: • Center • PS: 0 vs. 1 • Location of the tumor: head vs. other location of the primary tumor *Investigational use. Conroy T, et al. N Engl J Med. 2011;364:1817-25. PFS Gemcitabine Probability 1.00 FOLFIRINOX HR = 0.47, 95% CI (0.37-0.59) 0.75 P < 0.0001 0.50 Median PFS FOLFIRINOX: 6.4 mos Median PFS gemcitabine: 3.3 mos 0.25 0.00 0 3 6 9 12 15 18 21 24 27 30 33 36 0 1 0 1 0 0 0 0 0 0 0 0 Months Number at risk Gemcitabine 171 88 26 FOLFIRINOX 171 121 85 8 42 5 17 2 7 0 4 Reprinted with permission from Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825. Acknowledgement of Commercial Support This activity is supported by educational grants from Bayer HealthCare Pharmaceuticals, Onyx Pharmaceuticals, Celgene Corporation, Daiichi Sankyo, Inc., and Lilly. For further information concerning Lilly grant funding visit www.lillygrantoffice.com Copyright © 2014 Med-IQ®. All rights reserved.