Tgh talk

1. Early Detection, Screening andEarly Detection, Screening and
Chemoprevention ofChemoprevention of
Pancreatic CancerPancreatic Cancer
Jason Klapman, MDJason Klapman, MD
Associate MemberAssociate Member
Director of EndoscopyDirector of Endoscopy
GI Tumor ProgramGI Tumor Program
Moffitt Cancer CenterMoffitt Cancer Center

2. Pancreatic CancerPancreatic Cancer
 43,920 diagnosed in 201243,920 diagnosed in 2012
 37,390 pancreatic cancer deaths in 201237,390 pancreatic cancer deaths in 2012
 25% 1 yr survival25% 1 yr survival
 5% 5 yr survival5% 5 yr survival
 20% 5 yr survival for patients undergoing20% 5 yr survival for patients undergoing
resectionresection

3. Pancreatic CancerPancreatic Cancer
 Risk factorsRisk factors
SmokingSmoking
DiabetesDiabetes
Chronic PancreatitisChronic Pancreatitis
African AmericanAfrican American
Hereditary pancreatic cancer syndromesHereditary pancreatic cancer syndromes
Familial pancreatic cancer (FPC)Familial pancreatic cancer (FPC)

4. Risk of Pancreatic CancerRisk of Pancreatic Cancer
IndividualsIndividuals RiskRisk Age 50Age 50 Age 70Age 70
No HistoryNo History 11 0.05%0.05% 0.5%0.5%
BRCA 2BRCA 2
(Breast-Ovarian)(Breast-Ovarian)
3.5-103.5-10 0.5%0.5% 5%5%
P16P16
(FAMMM)(FAMMM)
20-3420-34 1%1% 10-17%10-17%
FamilialFamilial 14-3214-32 0.8-1.6%0.8-1.6% 8-16%8-16%
PRSS1PRSS1
(Pancreatitis)(Pancreatitis)
50-8050-80 2.5%2.5% 25-40%25-40%
STK11/LKB1STK11/LKB1
(Peutz-Jeghers)(Peutz-Jeghers)
132132 6.6%6.6% 30-60%30-60%

5. Familial PancreaticFamilial Pancreatic
Cancer(FPC)Cancer(FPC)
 DefinitionDefinition--At least 2 FDR affected withoutAt least 2 FDR affected without
accumulation of other cancers or familialaccumulation of other cancers or familial
diseasesdiseases
18-fold increase in relatives with 2 First-18-fold increase in relatives with 2 First-
Degree Relatives(FDR) affectedDegree Relatives(FDR) affected
57-fold increase in relatives with 3 family57-fold increase in relatives with 3 family
members affectedmembers affected
BRCA2 (17-19%)BRCA2 (17-19%)

6. Preliminary StudiesPreliminary Studies
 Canto et al at JHCanto et al at JH
Screened high-risk individuals using CTscan,Screened high-risk individuals using CTscan,
ERCP and EUS over a 2 stage 5 year periodERCP and EUS over a 2 stage 5 year period
78 patients screened revealed 8 significant78 patients screened revealed 8 significant
precancerous/ cancerous lesions that wereprecancerous/ cancerous lesions that were
surgically resected (Yield 10%)surgically resected (Yield 10%)

7. Protocol for High-Risk Assessment,Protocol for High-Risk Assessment,
Screening and Early Detection ofScreening and Early Detection of
Pancreatic Cancer by EndoscopicPancreatic Cancer by Endoscopic
UltrasoundUltrasound
PRINCIPAL INVESTIGATOR: JASON KLAPMAN, MDPRINCIPAL INVESTIGATOR: JASON KLAPMAN, MD
CO-INVESTIGATORS: MOKENGE MALAFA, MD;CO-INVESTIGATORS: MOKENGE MALAFA, MD;
PAMELA HODUL, MD;PAMELA HODUL, MD;
BARBARA CENTENO, MD;BARBARA CENTENO, MD;
CATHERINE PHELAN MD PhD;CATHERINE PHELAN MD PhD;
REBECCA SUTPHEN, MD; TOM SELLERS PhDREBECCA SUTPHEN, MD; TOM SELLERS PhD

8. PRIMARY OBJECTIVESPRIMARY OBJECTIVES
 To establish a cohort of individuals at high-riskTo establish a cohort of individuals at high-risk
for the development of pancreatic cancer.for the development of pancreatic cancer.
 To perform annual screening of these high-riskTo perform annual screening of these high-risk
individuals using Endoscopic Ultrasound (EUS).individuals using Endoscopic Ultrasound (EUS).
 To obtain self-reported risk factor questionnairesTo obtain self-reported risk factor questionnaires
on these high-risk individuals.on these high-risk individuals.
 To collect biospecimens (blood and urine) fromTo collect biospecimens (blood and urine) from
this cohort of high-risk individualsthis cohort of high-risk individuals

9. SECONDARY OBJECTIVESSECONDARY OBJECTIVES
 To determine whether targeted screening of theseTo determine whether targeted screening of these
high-risk individuals using Endoscopic Ultrasoundhigh-risk individuals using Endoscopic Ultrasound
(EUS) at regular intervals can detect precancerous(EUS) at regular intervals can detect precancerous
pancreas changes or early stage asymptomaticpancreas changes or early stage asymptomatic
pancreatic cancer.pancreatic cancer.
 To obtain permission from the study participants to useTo obtain permission from the study participants to use
their self-reported risk factors, biospecimens collectedtheir self-reported risk factors, biospecimens collected
and medical records obtained from the screeningand medical records obtained from the screening
program to identify patients who may be eligible forprogram to identify patients who may be eligible for
future clinical trials involving early detection andfuture clinical trials involving early detection and
chemoprevention of pancreatic cancerchemoprevention of pancreatic cancer

10. Study DesignStudy Design
 Eligibility CriteriaEligibility Criteria
 Pts with at least 2 FDR from a familial PC kindredPts with at least 2 FDR from a familial PC kindred
with 2 members affectedwith 2 members affected
 If more than 2 family members affected on the sameIf more than 2 family members affected on the same
side then the person being screened must have be aside then the person being screened must have be a
FDR of 1 of the membersFDR of 1 of the members
 Age >40 or 10yrs younger than youngest affectedAge >40 or 10yrs younger than youngest affected
 PJS patients age>30PJS patients age>30
 Familial Pancreatitis patientsFamilial Pancreatitis patients
 FAMMMFAMMM
 Pt’s with BRCA2 and Family Hx of Pancreatic CancerPt’s with BRCA2 and Family Hx of Pancreatic Cancer

11. Study DesignStudy Design
 Exclusion CriteriaExclusion Criteria
Age<18Age<18
Medical Contraindications to endoscopy orMedical Contraindications to endoscopy or
obstruction of GI tractobstruction of GI tract
Personal History of PancreaticPersonal History of Pancreatic
AdenocarcinomaAdenocarcinoma
Previous partial/complete resection of thePrevious partial/complete resection of the
pancreas for adenocarcinomapancreas for adenocarcinoma
Prior partial or total gastrectomy with B2 orPrior partial or total gastrectomy with B2 or
Roux-En-Y anastamosisRoux-En-Y anastamosis

12. EndoscopicEndoscopic Ultrasound(EUS)Ultrasound(EUS)
 Originally developed as an alternativeOriginally developed as an alternative
diagnostic imaging modality of thediagnostic imaging modality of the
pancreaspancreas
 Technological advances have broadenedTechnological advances have broadened
the field of Endoscopic Ultrasoundthe field of Endoscopic Ultrasound
 EUS-guided Fine-Needle Aspiration (FNA)EUS-guided Fine-Needle Aspiration (FNA)
 EUS-guided FNA of a pancreatic cancer inEUS-guided FNA of a pancreatic cancer in
first performed in 1994first performed in 1994

14. EUS EquipmentEUS Equipment

15. EUS Staging of Pancreatic CancerEUS Staging of Pancreatic Cancer
 Accuracy of TNM stagingAccuracy of TNM staging
T stage 74-94%T stage 74-94%
N stage 64-92%N stage 64-92%
M stage (occult liver metastasis)M stage (occult liver metastasis)
 EUS vs. Helical CTscanEUS vs. Helical CTscan
Sensitivity for detecting tumors 97% vs. 73%Sensitivity for detecting tumors 97% vs. 73%
Detects small tumors<2cm which are oftenDetects small tumors<2cm which are often
not seen on CTscannot seen on CTscan
Predicting vascular invasionPredicting vascular invasion

16. EUS-guided FNA in PancreaticEUS-guided FNA in Pancreatic
CancerCancer
 EUS-guided FNA of pancreatic massesEUS-guided FNA of pancreatic masses
Sensitivity 85-90%Sensitivity 85-90%
Specificity 97-100%Specificity 97-100%
Accuracy 84-92%Accuracy 84-92%
 False negative rate of ERCP and CT-False negative rate of ERCP and CT-
guided biopsies 20-30%guided biopsies 20-30%

17. R e p e a t E U S in 1 y r
N o rm a l
S u rg ic a l re fe rra l
R e s e c ta b le
R e fe rra l to O n c o lo g y
U n re s e c ta b le
P a n c re a tic a n d C h e s t C T
In v a s iv e o r p re -in v a s iv e n e o p la s m
R e p e a t E U S /F N A
6 m o n th s
B e n ig n
R e p e a t E U S
3 M o n th s
In d e te rm in a te
C y s t > 1 c m p e rfo rm F N A
M R I/M R C P 6 m o s
U n c h a n g e d s iz e
E U S F N A
In c re a s e d s iz e
R e p e a t E U S 3 m o s
C y s t< 1 c m
A b n o rm a l (M a s s /C y s t)
S c re e n in g E U S E x a m
G e n e tic C o u n s e lin g
C o n s e n t F o r P a n c re a tic S c re e n in g P ro to c o l
H ig h -ris k In d iv id u a l Id e n tifie d
M o ffitt P a tie n ts /T u m o r re g is try /P h y s ic ia n R e fe rra ls / L ife tim e

18. Accrual (Jan 2012)Accrual (Jan 2012)
 41 patients accrued so far41 patients accrued so far
20 patients with 2 FDR’s affected20 patients with 2 FDR’s affected
8 patients with 3 FDR’s affected8 patients with 3 FDR’s affected
7 patients with 1 FDR and at least 3 affected7 patients with 1 FDR and at least 3 affected
individuals on the same side of familyindividuals on the same side of family
6 patients with BRCA2 and FDR or SDR6 patients with BRCA2 and FDR or SDR
diagnosed with pancreatic cancerdiagnosed with pancreatic cancer

19. Preliminary ResultsPreliminary Results
41 patients
screened
27 Normal EUS 14 Abnormal
Surveillance Arm
2-2 large cysts
FNA-IPMN
12 at least one
<1cm cyst
F/U EUS/MRCP2 Surgery

20. Incidental FindingsIncidental Findings
 1 patient had asymptomatic1 patient had asymptomatic
choledocholithiasis- s/p ERCP stonecholedocholithiasis- s/p ERCP stone
extractionextraction
 1 patient had a large duodenal adenoma1 patient had a large duodenal adenoma
s/p surgical excisions/p surgical excision
 1 patient had a non-functioning islet cell1 patient had a non-functioning islet cell
tumor of the pancreastumor of the pancreas

21. Study Conclusions/QuestionsStudy Conclusions/Questions
 Screening high risk individuals (HRI) is feasibleScreening high risk individuals (HRI) is feasible
and safe using EUS aloneand safe using EUS alone
 Whether screening (HRI) actually impactsWhether screening (HRI) actually impacts
survival of these patients is yet to be determinedsurvival of these patients is yet to be determined
 Significant findings were multiple cysts inSignificant findings were multiple cysts in
patients most likely IPMN side branch typepatients most likely IPMN side branch type
 What is the risk of transformation to malignancy inWhat is the risk of transformation to malignancy in
this patient population?this patient population?
 Should screening be one time or should patients beShould screening be one time or should patients be
followed?followed?
 What is the best way to screen? EUS? CT?What is the best way to screen? EUS? CT?
MRI? CA-19-9?MRI? CA-19-9?

22. How to screen?How to screen?
 Zubarik et al. GIE July 2011Zubarik et al. GIE July 2011
 Screened 546 with at least 1 FDR with pancreatic withScreened 546 with at least 1 FDR with pancreatic with
CA 19-9 and then EUS was performed if elevatedCA 19-9 and then EUS was performed if elevated
 27(4.9%) elevated CA 19-9 (>37)27(4.9%) elevated CA 19-9 (>37)
 Neoplastic or malignant findings were found in 5 patientsNeoplastic or malignant findings were found in 5 patients
 1Stage 1 pancreatic cancer (.2%)1Stage 1 pancreatic cancer (.2%)
 1 NET1 NET
 1 IPMN1 IPMN
 1 Mucinous neoplasm1 Mucinous neoplasm
 1 PanIN1 lesion1 PanIN1 lesion
 Cost to detect neoplasia was $8431 and to detect pancreaticCost to detect neoplasia was $8431 and to detect pancreatic
cancer $41,133cancer $41,133

23. How to screen?How to screen?
 Canto et al. Gastro 2012 (In press)Canto et al. Gastro 2012 (In press)
 225 high-risk patients screening with CT, MRI and EUS225 high-risk patients screening with CT, MRI and EUS
 92/225 (42%) had at least 1 pancreatic mass (84 cystic,3 solid) or a92/225 (42%) had at least 1 pancreatic mass (84 cystic,3 solid) or a
dilated PD (5)dilated PD (5)
 51 had multiple cysts mean size 5mm (2-39mm))51 had multiple cysts mean size 5mm (2-39mm))
 CT,MRI and EUS detected a pancreatic abnormality in 11%,33.3%CT,MRI and EUS detected a pancreatic abnormality in 11%,33.3%
and 42.6% of HRIand 42.6% of HRI
 CT least sensitive while MRI and EUS concordance rate wasCT least sensitive while MRI and EUS concordance rate was
91%( MRI missed 11 cysts seen by EUS and EUS missed 491%( MRI missed 11 cysts seen by EUS and EUS missed 4
cysts seen on MRI)cysts seen on MRI)
 Conclusion-Conclusion-
 screening detects small pancreatic cysts, including curablescreening detects small pancreatic cysts, including curable
noninvasive high-grade neoplasm'snoninvasive high-grade neoplasm's
 Screening should be initiated at age 50 not 40Screening should be initiated at age 50 not 40

24. Summary of studiesSummary of studies
 MRI and EUS are both excellent screeningMRI and EUS are both excellent screening
modalities to pick up small side-branch IPMNsmodalities to pick up small side-branch IPMNs
 MRI less invasive and may ultimately be theMRI less invasive and may ultimately be the
initial screening modality followed by EUS ifinitial screening modality followed by EUS if
there are any abnormalities amenable to FNAthere are any abnormalities amenable to FNA
 One time screening vs surveillance needs to beOne time screening vs surveillance needs to be
further investigatedfurther investigated
 Multicenter international studies are needed toMulticenter international studies are needed to
further answer the question of whetherfurther answer the question of whether
screening ultimately impacts survival in HRIscreening ultimately impacts survival in HRI

25. Chemoprevention trials inChemoprevention trials in
pancreatic cancerpancreatic cancer

26. Tocotrienols in Pancreatic CancerTocotrienols in Pancreatic Cancer
Preclinical studiesPreclinical studies
 Delta-tocotrienol was the most effective vitaminDelta-tocotrienol was the most effective vitamin
E compound against pancreatic cancer.E compound against pancreatic cancer.
 Mice receiving delta-tocotrienol showedMice receiving delta-tocotrienol showed
pancreatic tumor growth inhibition.pancreatic tumor growth inhibition.
 Adequate levels of delta-tocotrienol in theAdequate levels of delta-tocotrienol in the
pancreas of mice was achieved with wellpancreas of mice was achieved with well
tolerated oral dosing.tolerated oral dosing.

27. Vitamin E TocotrienolsVitamin E Tocotrienols
Food SourcesFood Sources
Palm WheatRice RyeBarley Oat

28. The hypothesisThe hypothesis
 Vitamin E delta-tocotrienol will activate cellVitamin E delta-tocotrienol will activate cell
death and decrease proliferation ofdeath and decrease proliferation of
pancreatic neoplastic cells therebypancreatic neoplastic cells thereby
resulting in the inhibition or delay ofresulting in the inhibition or delay of
pancreatic tumor growth.pancreatic tumor growth.

29. Phase I Study of Vitamin EPhase I Study of Vitamin E δδ-Tocotrienol-Tocotrienol
in Pancreatic Neoplasiain Pancreatic Neoplasia
 Single center, open label, dose-escalation study.Single center, open label, dose-escalation study.
 Approximately 45 patients with pancreaticApproximately 45 patients with pancreatic
tumors undergoing surgery will be enrolled.tumors undergoing surgery will be enrolled.
 14 day treatment oral dosing14 day treatment oral dosing
 17 patients enrolled to date in the dose17 patients enrolled to date in the dose
escalation phase last dose (1600mg bid)escalation phase last dose (1600mg bid)
 Objectives-PK,PD tumor and normal pancreasObjectives-PK,PD tumor and normal pancreas
evaluated for apoptosis and drug levels, MTDevaluated for apoptosis and drug levels, MTD
phasephase

30. Phase I Dose-Escalation Study of the Safety and
Pharmacokinetics of Vitamin E δ-
Tocotrienol Following Single Dose Administration in
Healthy Subjects
 The primary objective
 1. To characterize the safety and tolerability of
Vitamin E δ-Tocotrienol when orally administered as a
single dose at dose levels (200, 400, 600, 800, 1200,
or 1600mg) in healthy subjects.
 The secondary objectives
 1. To determine the effects of dose on the plasma
pharmacokinetic (PK) of Vitamin E δ-Tocotrienol
when orally administered as a single dose in healthy
subjects.
 2. To evaluate pharmacodynamic (PD) markers of
Vitamin E δ-Tocotrienol activity in peripheral blood.

31. Phase I Dose-Escalation Study of the Safety and
Pharmacokinetics of Vitamin E δ-
Tocotrienol Following Multiple Dose Administration in
Healthy Subjects
 The primary objective
 1. To characterize the safety and tolerability of
Vitamin E δ-Tocotrienol when orally administered at
up to 5.6 times the predicted biological effective dose
(1600mg twice daily) for 14 consecutive days in
healthy subjects.
 The secondary objectives
 1. To determine the effects of dose on the plasma
pharmacokinetic (PK) of Vitamin E δ-Tocotrienol
following multiple dose administration in healthy
subjects.
 2. To evaluate pharmacodynamic (PD) markers of
Vitamin E δ-Tocotrienol activity in peripheral blood.

32. Strategy For InvestigatingStrategy For Investigating δδ-Tocotrienol-Tocotrienol InIn
Pancreatic CancerPancreatic Cancer
Phase 0/I ‘Proof of Concept’ trials in:
• Patients undergoing surgical resection.
•Patients who have had resection.
•Healthy subjects.
Phase II/III trials in:
•Patients with resected Pancreatic Ca.
Phase III trials in:
•Heritable syndromes.
•Incidental pre-neoplastic tumors

33. SummarySummary
 There is no good gold standard screeningThere is no good gold standard screening
tool for pancreatic cancer that is cost-tool for pancreatic cancer that is cost-
effective for the general populationeffective for the general population
 Screening should target HRIScreening should target HRI
 Research efforts should be focused onResearch efforts should be focused on
chemoprevention, screening and earlychemoprevention, screening and early
detection to ultimately have an impact ondetection to ultimately have an impact on
pancreatic cancerpancreatic cancer

34. AcknowledgementsAcknowledgements
 Mo Malafa, MDMo Malafa, MD
 Gregory Springett, MDGregory Springett, MD
 Tiffany Campos 745-8358 pancreaticTiffany Campos 745-8358 pancreatic
screening trialscreening trial
 Helen Jump 745-4834 Vitamin E delta-Helen Jump 745-4834 Vitamin E delta-
tocotrienol trialstocotrienol trials