FacultyCaio 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 PlannersShari J. Dermer, PhD
Manager, Educational Strategy and Content
Med-IQ
Baltimore, MD
Lisa R. Rinehart, MS, ELS
Director, Editorial Services
Med-IQ
Baltimore, MD
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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
www.SEER.cancer.gov.
Nu
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ers
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s
Time From Induction, months
|1992
|2010
|1995
|2000
|2005
New CasesDeaths
Localized (9%)Confined to primary site
Regional (27%)Spread to regional lymph nodes
Distant (53%)Cancer has metastasized
Unknown (11%)Unstaged
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
Study
Radiation
(Gy) ChemoNo. of
Patients
Median Survival
(Mos)1-Year
Survival (%)
ECOG1
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
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.*Investigational
FOLFIRINOX* Experience in LAPC
Hosein P, et al. BMC Cancer. 2012;12:199.
n (%)Age Median (range) 57.5 (41-73)Sex
Male 10 (56%)Female 8 (44%)
ECOG Performance Status0 8 (44%)1 10 (56%)
Pancreatic tumor locationHead 11 (61%)
Uncinate process 3 (17%)Body 2 (11%)Tail 2 (11%)
Biliary stentYes 9 (50%)No 9 (50%)
Basis for unresectabilitySMA encased 3 (17%)HA encased 2 (11%)
Celiac trunk encased 3 (17%)Confluence of PV, SV and
SMV encaed 5( 28%)SMV encaed 4 (22%)SV encased 1 (6%)
*Investigational use.
FOLFIRINOX* Outcomes in LAPC
4 still unresectable
3 resectable by imaging
3 R0resections
3 post-opcombined
chemoradiation
1 post-opobservation
14 patientsFOLFIRINOX(3-12 cycles)
9 unresectable at maximum response or tolerability
Combinedchemoradiation
(2 ongoing)
1 progressed after 3 cycles
4 resectable by imaging2 R0 resections1 R1 resection
1 unresectable at E-lap
1 still unresectable
4 patientsFOLFIRINOX(6-17 cycles)
1 unresectable at maximum response or tolerability
Combinedchemoradiation
3 post-opcombined
chemoradiation
3 resectable by imaging3 R0 resections
Patient flowchart for patients assessed as having unresectable disease (panel A, n = 14), and for those assessed as having borderline resectable disease (panel B). Hosein P, et al. BMC Cancer. 2012;12:199.
A B
*Investigational use.
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
Outcome
Nab-PacGemcitabine
n = 431Gemcitabine
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 median5.5
(4.47-5.95)3.7
(3.61-4.04)0.69
(0.581-0.821)0.000024
RR % 23 7 -
Von Hoff DD, et al. GI Cancers Symposium 2013[Abstract LBA148].
PRODIGE 4—ACCORD 11 Trial Design
Stratification:• Center• PS: 0 vs. 1• Location of the tumor: head vs. other location of the primary
tumor
Metastaticpancreaticcancer
FOLFIRINOX*
Gemcitabine
6 months of chemotherapy recommended
CT scans: obtained every 2 months
For both arms:RANDOMIZE
Conroy T, et al. N Engl J Med. 2011;364:1817-25.*Investigational use.
PFS
Median PFS FOLFIRINOX: 6.4 mos
Median PFS gemcitabine: 3.3 mos
0.00
0.25
0.50
0.75
1.00
Pro
bab
ility
171 121 85 42 17 7 4 1 1 0 0 0 0FOLFIRINOX171 88 26 8 5 2 0 0 0 0 0 0 0Gemcitabine
Number at risk
0 3 6 9 12 15 18 21 24 27 30 33 36
Months
Gemcitabine
FOLFIRINOX
P < 0.0001
HR = 0.47, 95% CI (0.37-0.59)
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 SupportThis 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
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