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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er

pe

r 1

00

,00

0 P

ers

on

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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