Early Detection, Screening and Early Detection, Screening and Chemoprevention of Chemoprevention of Pancreatic CancerPancreatic Cancer

Jason Klapman, MDJason Klapman, MDAssociate MemberAssociate Member

Director of EndoscopyDirector of EndoscopyGI Tumor ProgramGI Tumor Program

Moffitt Cancer CenterMoffitt Cancer Center

Pancreatic Cancer Pancreatic Cancer

43,920 diagnosed in 201243,920 diagnosed in 201237,390 pancreatic cancer deaths in 201237,390 pancreatic cancer deaths in 201225% 1 yr survival25% 1 yr survival5% 5 yr survival5% 5 yr survival20% 5 yr survival for patients undergoing 20% 5 yr survival for patients undergoing

resectionresection

Pancreatic CancerPancreatic Cancer

Risk factorsRisk factorsSmoking Smoking Diabetes Diabetes Chronic Pancreatitis Chronic Pancreatitis African AmericanAfrican AmericanHereditary pancreatic cancer syndromesHereditary pancreatic cancer syndromesFamilial pancreatic cancer (FPC)Familial pancreatic cancer (FPC)

Risk of Pancreatic CancerRisk of Pancreatic CancerIndividualsIndividuals 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%

PRSS1 PRSS1 (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%

Familial Pancreatic Familial Pancreatic Cancer(FPC)Cancer(FPC)

DefinitionDefinition--At least 2 FDR affected without At least 2 FDR affected without accumulation of other cancers or familial accumulation of other cancers or familial diseasesdiseases18-fold increase in relatives with 2 First-18-fold increase in relatives with 2 First-

Degree Relatives(FDR) affectedDegree Relatives(FDR) affected57-fold increase in relatives with 3 family 57-fold increase in relatives with 3 family

members affectedmembers affectedBRCA2 (17-19%)BRCA2 (17-19%)

Preliminary StudiesPreliminary Studies

Canto et al at JHCanto et al at JHScreened 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 period78 patients screened revealed 8 significant 78 patients screened revealed 8 significant

precancerous/ cancerous lesions that were precancerous/ cancerous lesions that were surgically resected (Yield 10%)surgically resected (Yield 10%)

Protocol for High-Risk Assessment, Protocol for High-Risk Assessment, Screening and Early Detection of Screening and Early Detection of Pancreatic Cancer by Endoscopic Pancreatic 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

PRIMARY OBJECTIVESPRIMARY OBJECTIVES

To establish a cohort of individuals at high-risk To 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-risk To perform annual screening of these high-risk individuals using Endoscopic Ultrasound (EUS).individuals using Endoscopic Ultrasound (EUS).

To obtain self-reported risk factor questionnaires To obtain self-reported risk factor questionnaires on these high-risk individuals.on these high-risk individuals.

To collect biospecimens (blood and urine) from To collect biospecimens (blood and urine) from this cohort of high-risk individuals this cohort of high-risk individuals

SECONDARY OBJECTIVESSECONDARY OBJECTIVES

To determine whether targeted screening of these To determine whether targeted screening of these high-risk individuals using Endoscopic Ultrasound high-risk individuals using Endoscopic Ultrasound (EUS) at regular intervals can detect precancerous (EUS) at regular intervals can detect precancerous pancreas changes or early stage asymptomatic pancreas changes or early stage asymptomatic pancreatic cancer. pancreatic cancer.

To obtain permission from the study participants to use To obtain permission from the study participants to use their self-reported risk factors, biospecimens collected their self-reported risk factors, biospecimens collected and medical records obtained from the screening and medical records obtained from the screening program to identify patients who may be eligible for program to identify patients who may be eligible for future clinical trials involving early detection and future clinical trials involving early detection and chemoprevention of pancreatic cancerchemoprevention of pancreatic cancer

Study DesignStudy Design

Eligibility CriteriaEligibility Criteria Pts with at least 2 FDR from a familial PC kindred with Pts with at least 2 FDR from a familial PC kindred with

2 members affected 2 members affected If more than 2 family members affected on the same If more than 2 family members affected on the same

side then the person being screened must have be a side 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

Study DesignStudy Design

Exclusion CriteriaExclusion CriteriaAge<18Age<18Medical Contraindications to endoscopy or Medical Contraindications to endoscopy or

obstruction of GI tract obstruction of GI tract Personal History of Pancreatic Personal History of Pancreatic

AdenocarcinomaAdenocarcinomaPrevious partial/complete resection of the Previous partial/complete resection of the

pancreas for adenocarcinomapancreas for adenocarcinomaPrior partial or total gastrectomy with B2 or Prior partial or total gastrectomy with B2 or

Roux-En-Y anastamosisRoux-En-Y anastamosis

EndoscopicEndoscopic Ultrasound(EUS)Ultrasound(EUS)

Originally developed as an Originally developed as an alternative diagnostic imaging alternative diagnostic imaging modality of the pancreas modality of the pancreas

Technological advances have Technological advances have broadened the field of Endoscopic broadened the field of Endoscopic UltrasoundUltrasound

EUS-guided Fine-Needle Aspiration (FNA)EUS-guided Fine-Needle Aspiration (FNA) EUS-guided FNA of a pancreatic cancer EUS-guided FNA of a pancreatic cancer

in first performed in 1994in first performed in 1994

EUS EquipmentEUS Equipment

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 CTscanSensitivity for detecting tumors 97% vs. 73%Sensitivity for detecting tumors 97% vs. 73%Detects small tumors<2cm which are often Detects small tumors<2cm which are often

not seen on CTscannot seen on CTscanPredicting vascular invasionPredicting vascular invasion

EUS-guided FNA in Pancreatic EUS-guided FNA in Pancreatic CancerCancer

EUS-guided FNA of pancreatic massesEUS-guided FNA of pancreatic massesSensitivity 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%

R e p e a t E U S in 1 yr

N o rm a l

S u rg ica l re fe rra l

R e sec ta b le

R e fe rra l to O n co lo gy

U n re sec ta b le

P a n cre a tic a n d C h es t C T

In va sive o r p re -in vas ive n e op la sm

R e p ea t E U S /F N A6 m o nths

B e n ign

R e p e a t E U S3 M on ths

In de te rm ina te

C ys t > 1 cm pe rfo rm F N A

M R I/M R C P 6 m os

U n ch a ng e d s ize

E U S F N A

In c rea se d s ize

R e p ea t E U S 3m os

C ys t< 1 cm

A b n o rm a l (M a ss /C ys t)

S c re en in g E U S E xam

G e n etic C o u nse ling

C o n se n t Fo r P a n c rea tic S c ree n in g P ro to co l

H ig h -risk Ind iv id ua l Id en tif ied

M o ffitt P a tie n ts /T u m o r re g is try/P h ys ic ian R e fe rra ls / L ife t im e

Accrual (Jan 2012)Accrual (Jan 2012)

41 patients accrued so far41 patients accrued so far20 patients with 2 FDR’s affected20 patients with 2 FDR’s affected8 patients with 3 FDR’s affected8 patients with 3 FDR’s affected7 patients with 1 FDR and at least 3 affected 7 patients with 1 FDR and at least 3 affected

individuals on the same side of familyindividuals on the same side of family6 patients with BRCA2 and FDR or SDR 6 patients with BRCA2 and FDR or SDR

diagnosed with pancreatic cancerdiagnosed with pancreatic cancer

Preliminary ResultsPreliminary Results41 patients screened

27 Normal EUS 14 Abnormal

Surveillance Arm2-2 large cysts

FNA-IPMN12 at least one

<1cm cyst

F/U EUS/MRCP2 Surgery

Incidental FindingsIncidental Findings

1 patient had asymptomatic 1 patient had asymptomatic choledocholithiasis- s/p ERCP stone choledocholithiasis- s/p ERCP stone extractionextraction

1 patient had a large duodenal adenoma 1 patient had a large duodenal adenoma s/p surgical excisions/p surgical excision

1 patient had a non-functioning islet cell 1 patient had a non-functioning islet cell tumor of the pancreastumor of the pancreas

Study Conclusions/QuestionsStudy Conclusions/Questions Screening high risk individuals (HRI) is feasible Screening high risk individuals (HRI) is feasible

and safe using EUS aloneand safe using EUS alone Whether screening (HRI) actually impacts Whether 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 in Significant 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 in this What is the risk of transformation to malignancy in this

patient population?patient population? Should screening be one time or should patients be Should 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?

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 with Screened 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 pancreatic Cost to detect neoplasia was $8431 and to detect pancreatic cancer $41,133cancer $41,133

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 a 92/225 (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 was CT least sensitive while MRI and EUS concordance rate was 91%( MRI missed 11 cysts seen by EUS and EUS missed 4 91%( 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 curable screening 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

Summary of studiesSummary of studies

MRI and EUS are both excellent screening MRI 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 the MRI less invasive and may ultimately be the initial screening modality followed by EUS if initial 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 be One time screening vs surveillance needs to be further investigatedfurther investigated

Multicenter international studies are needed to Multicenter international studies are needed to further answer the question of whether further answer the question of whether screening ultimately impacts survival in HRIscreening ultimately impacts survival in HRI

Chemoprevention trials in Chemoprevention trials in pancreatic cancerpancreatic cancer

Tocotrienols in Pancreatic CancerTocotrienols in Pancreatic Cancer Preclinical studiesPreclinical studies

Delta-tocotrienol was the most effective vitamin Delta-tocotrienol was the most effective vitamin E compound against pancreatic cancer.E compound against pancreatic cancer.

Mice receiving delta-tocotrienol showed Mice receiving delta-tocotrienol showed pancreatic tumor growth inhibition.pancreatic tumor growth inhibition.

Adequate levels of delta-tocotrienol in the Adequate levels of delta-tocotrienol in the pancreas of mice was achieved with well pancreas of mice was achieved with well tolerated oral dosing.tolerated oral dosing.

Vitamin E TocotrienolsVitamin E TocotrienolsFood SourcesFood Sources

Palm WheatRice RyeBarley Oat

The hypothesisThe hypothesis

Vitamin E delta-tocotrienol will activate cell Vitamin E delta-tocotrienol will activate cell death and decrease proliferation of death and decrease proliferation of pancreatic neoplastic cells thereby pancreatic neoplastic cells thereby resulting in the inhibition or delay of resulting in the inhibition or delay of pancreatic tumor growth.pancreatic tumor growth.

Phase I Study of Vitamin E Phase 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 pancreatic Approximately 45 patients with pancreatic

tumors undergoing surgery will be enrolled.tumors undergoing surgery will be enrolled. 14 day treatment oral dosing 14 day treatment oral dosing 17 patients enrolled to date in the dose 17 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 pancreas Objectives-PK,PD tumor and normal pancreas

evaluated for apoptosis and drug levels, MTD evaluated for apoptosis and drug levels, MTD phasephase

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.

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.

Strategy For Investigating Strategy For Investigating δδ-Tocotrienol-Tocotrienol In In 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

SummarySummary

There is no good gold standard screening There 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 HRIResearch efforts should be focused on Research efforts should be focused on

chemoprevention, screening and early chemoprevention, screening and early detection to ultimately have an impact on detection to ultimately have an impact on pancreatic cancer pancreatic cancer

AcknowledgementsAcknowledgements

Mo Malafa, MDMo Malafa, MDGregory Springett, MDGregory Springett, MDTiffany Campos 745-8358 pancreatic Tiffany Campos 745-8358 pancreatic

screening trialscreening trialHelen Jump 745-4834 Vitamin E delta-Helen Jump 745-4834 Vitamin E delta-

tocotrienol trialstocotrienol trials