Early diagnosis of pancreatic Early diagnosis of pancreatic cancercancer

Moderators:Moderators:

Banke Agarwal, MDBanke Agarwal, MD

David Linehan, MDDavid Linehan, MD

Panelists:Panelists:

Suresh Chari, MDSuresh Chari, MD

Michael Goggins, MDMichael Goggins, MD

David Whitcombe, MDDavid Whitcombe, MD

Maurits Weirsema, MDMaurits Weirsema, MD

Why is early diagnosis Why is early diagnosis desirabledesirable

Despite considerable investment in Despite considerable investment in improving therapy, the outcomes in improving therapy, the outcomes in pancreatic cancer have not changed pancreatic cancer have not changed much in past several decadesmuch in past several decades

Approximately 85% of patients have Approximately 85% of patients have Stage IV disease at the time of initial Stage IV disease at the time of initial presentationpresentation

Baxter et al, Ann Surg Oncol 2007

Why is early diagnosis desirable?

Baxter et al, SEER database

The outcomes in patients with The outcomes in patients with smaller tumors are consistently smaller tumors are consistently better than those with larger better than those with larger tumors in several published tumors in several published studiesstudies

Agarwal et al Pancreas 2008

Survival and resectability in patients with pancreatic cancer based on tumor size

17.2

12.3

8.5

7.6

83

67

36

7

0

5

10

15

20

25

30

≤20 mm 21-25 mm 26-30 mm ≥31 mm

tumor size

med

ian

surv

ival

(mth

s)

0

10

20

30

40

50

60

70

80

90

% re

sect

able

Median survival

resectability

Washington University Pancreas Cancer Database2000-2007(unpublished)

N=540

Size of pancreatic tumor at diagnosis Size of pancreatic tumor at diagnosis over past few decadesover past few decades

First authorFirst author Year of Year of publicationpublication

Patient Patient accrualaccrual

InstitutionInstitution Mean tumor Mean tumor sizesize

FortnerFortner 19961996 1979-19911979-1991 MSKCCMSKCC 3.9 cm3.9 cm

Yeo Yeo 19951995 1970-19941970-1994 JHMIJHMI 3.0 cm3.0 cm

Nitecki Nitecki 19951995 1981-19911981-1991 MayoMayo 3.1 cm3.1 cm

Sohn Sohn 20012001 1984-19991984-1999 JHMIJHMI 3.2 cm3.2 cm

Schmidt Schmidt 20042004 1980-20021980-2002 IUPUIIUPUI 3.2 cm3.2 cm

Agarwal Agarwal 20042004 2000-20022000-2002 MDACCMDACC 3.0 cm3.0 cm

Why are we not diagnosing Why are we not diagnosing early cancers despite early cancers despite improvements in imaging?improvements in imaging?

Patients with early cancers are usually Patients with early cancers are usually asymptomatic and do not present for asymptomatic and do not present for medical attentionmedical attention

Early cancers noted in asymptomatic Early cancers noted in asymptomatic patients are often overlooked by patients are often overlooked by radiologistsradiologists

Gangi et al AJR 2004

Findings suggestive of pancreatic cancer in CT scans performed prior to diagnosis of Pancreatic Cancer

0

20

40

60

80

100

120

0-2 mths(n=15)

2-6 mths(n=6)

6-18 mths(n=8)

>18 mths(n=15)

Time of CT prior to diagnosis of Pancreatic Cancer

sen

sitiv

ity %

Observer 1

Observer 2

both agree onpresence of tumor

Why renewed emphasis on Why renewed emphasis on early diagnosis now?early diagnosis now?

– Improved resolution with CT/MRIImproved resolution with CT/MRI– Advent of EUS-FNA to provide Advent of EUS-FNA to provide

cytologic diagnosis in patients with cytologic diagnosis in patients with early stage pancreatic cancersearly stage pancreatic cancers

– Advances in molecular testing Advances in molecular testing – Better understanding of pathogenesis Better understanding of pathogenesis

and natural history of pancreatic and natural history of pancreatic cancercancer

– Less nihilism?Less nihilism?

Attempts at early Attempts at early diagnosis of diagnosis of pancreatic cancerpancreatic cancer

pancreatic pancreatic cancer cancer screeningscreening

=???

Is there an identifiable prodrome? Can we identify an at-risk population?

Characteristics of diseases Characteristics of diseases amenable to screeningamenable to screening

1.1. Substantial morbidity or mortality if Substantial morbidity or mortality if untreateduntreated

2.2. High clinical prevalenceHigh clinical prevalence– High risk populationsHigh risk populations

3.3. Existence of critical point and Existence of critical point and appropriate therapyappropriate therapy

4.4. Low incidence of pseudo-diseaseLow incidence of pseudo-disease

What speaks against What speaks against screening?screening? Harm due to screeningHarm due to screening

– ComplicationsComplications– OvertreatmentOvertreatment

Low yield/costLow yield/cost No proof that stage migration No proof that stage migration

results in improved outcomeresults in improved outcome

Q. Is there a good case for Q. Is there a good case for screening pancreatic cancerscreening pancreatic cancer

In general population?In general population?

Incidence is 1 in 100,000Incidence is 1 in 100,000

In high risk patient groups?In high risk patient groups?

Prevalence of cancers Prevalence of cancers that are currently that are currently screenedscreened Colon cancer -Colon cancer - Breast cancer -Breast cancer - Lung cancer ? -Lung cancer ? - Cervical cancer -Cervical cancer - Prostate cancer -Prostate cancer -

Characteristics of screening Characteristics of screening testtest

1.1. Test accuracyTest accuracy

2.2. Test reproducibilityTest reproducibility

3.3. Test safety, availability and cost Test safety, availability and cost effectivenesseffectiveness

Which tests are best potential Which tests are best potential candidates for pancreatic candidates for pancreatic cancer screeningcancer screening

1.1. Serum markersSerum markers

2.2. Cross sectional imaging with spiral Cross sectional imaging with spiral CT or MRICT or MRI

3.3. EUS/FNAEUS/FNA

4.4. ERCPERCP

5.5. Abdominal USAbdominal US

6.6. None of the aboveNone of the above

Potential strategies for Potential strategies for diagnosing pancreatic diagnosing pancreatic cancer in early stagescancer in early stages Identification of high risk groups for Identification of high risk groups for

screeningscreening Screening/surveillance of patients with Screening/surveillance of patients with

familial or environmental familial or environmental predispositionpredisposition

Development of molecular biomarkers Development of molecular biomarkers for screening or identifying high risk for screening or identifying high risk populationpopulation

Enriched populations for screening Enriched populations for screening for pancreatic cancerfor pancreatic cancerSuresh Chari- 10 minSuresh Chari- 10 min

Are there any enriched population subsets with higher Are there any enriched population subsets with higher prevalence of pancreatic cancer?prevalence of pancreatic cancer?– New onset diabetes mellitusNew onset diabetes mellitus– Idiopathic acute pancreatitis in the elderlyIdiopathic acute pancreatitis in the elderly– New diagnosis of chronic pancreatitisNew diagnosis of chronic pancreatitis– New onset unipolar depression in the elderlyNew onset unipolar depression in the elderly

What percentage of pancreatic cancers have associated What percentage of pancreatic cancers have associated above presentations?above presentations?

What percentage of patients with above presentations have What percentage of patients with above presentations have pancreatic cancer?pancreatic cancer?

Can we further enrich above populations based on:Can we further enrich above populations based on:– Age, h/o smokingAge, h/o smoking– Further defining the clinical syndromeFurther defining the clinical syndrome– Use of serum markersUse of serum markers

Familial pancreatic cancersFamilial pancreatic cancersDavid Whitcomb 10 minsDavid Whitcomb 10 mins

What proportion of pancreatic cancers are familial?What proportion of pancreatic cancers are familial? What is the risk of pancreatic cancer in various What is the risk of pancreatic cancer in various

familial conditions?familial conditions? What are the familial conditions where surveillance What are the familial conditions where surveillance

for pancreatic cancer would seem justified?for pancreatic cancer would seem justified? What are the currently available means for What are the currently available means for

evaluating these patients for pancreatic cancer and evaluating these patients for pancreatic cancer and how effective are they?how effective are they?

Will lessons learned in familial cancers apply to Will lessons learned in familial cancers apply to sporadic ones?sporadic ones?

Molecular markers to aid in early Molecular markers to aid in early diagnosis of pancreatic cancerdiagnosis of pancreatic cancerMichael Goggins 10 minsMichael Goggins 10 mins

What will be the required performance What will be the required performance characteristics of a serum molecular marker to becharacteristics of a serum molecular marker to be– Useful in screening of pancreatic cancerUseful in screening of pancreatic cancer– Diagnosis of pancreatic cancerDiagnosis of pancreatic cancer– PrognosticationPrognostication

Are there any molecular markers in the horizon Are there any molecular markers in the horizon that can potentially be used for above purposes?that can potentially be used for above purposes?

What is the current state of the art in What is the current state of the art in development of biomarkers for pancreatic development of biomarkers for pancreatic cancer?cancer?

Is there a precursor in pancreatic cancer Is there a precursor in pancreatic cancer carcinogenesis (analogous to HGD e.g.,PanIN3) carcinogenesis (analogous to HGD e.g.,PanIN3) that can be reliably diagnosed pre-operatively.that can be reliably diagnosed pre-operatively.

How can EUS/FNA help in early How can EUS/FNA help in early diagnosis of pancreatic cancerdiagnosis of pancreatic cancerMaurits Wiersema 10 minsMaurits Wiersema 10 mins

What are the performance characteristics of EUS-FNA for What are the performance characteristics of EUS-FNA for identifying and diagnosing early tumors?identifying and diagnosing early tumors?

How does EUS/FNA compare with CT or MRI for diagnosis How does EUS/FNA compare with CT or MRI for diagnosis of early cancers?of early cancers?

What is the risk of complications with EUS and EUS-FNA?What is the risk of complications with EUS and EUS-FNA? Can EUS potentially be used for detecting and diagnosing Can EUS potentially be used for detecting and diagnosing

pancreatic cancer in enriched population subsets?pancreatic cancer in enriched population subsets? Role of EUS in diagnosing cancer in patients with Role of EUS in diagnosing cancer in patients with

subtle/non-specific findings suggestive of cancer on CT subtle/non-specific findings suggestive of cancer on CT scan/MRI?scan/MRI?

Are there workforce issues if screening became generally Are there workforce issues if screening became generally accepted?accepted?

Is there a realistic mechanism for quality control?Is there a realistic mechanism for quality control?

What are the performance What are the performance characteristics of EUS-FNA for characteristics of EUS-FNA for identifying and diagnosing identifying and diagnosing early tumors?early tumors? EUS is more sensitive than MDCT for EUS is more sensitive than MDCT for

tumor detection (98% vs 86%) with a tumor detection (98% vs 86%) with a more marked difference in smaller more marked difference in smaller tumors – DeWitt 2004 Ann Intern Med tumors – DeWitt 2004 Ann Intern Med

Operating characteristics for EUS in Operating characteristics for EUS in precursor lesions is unknown – Canto precursor lesions is unknown – Canto 2006 CGH, Kimmey 2002 GIE2006 CGH, Kimmey 2002 GIE– PanIN equivalents – are changes of chronic PanIN equivalents – are changes of chronic

pancreatitis a surrogate?pancreatitis a surrogate?– IPMNIPMN– < 1 cm masses< 1 cm masses

What are the performance What are the performance characteristics of EUS-FNA for characteristics of EUS-FNA for identifying and diagnosing identifying and diagnosing early tumors?early tumors? 72% of high risk patients have features 72% of high risk patients have features

of chronic pancreatitis vs 14% of controlsof chronic pancreatitis vs 14% of controls 25% of patients in high risk kindreds will 25% of patients in high risk kindreds will

have a ‘neoplastic’ abnormality on initial have a ‘neoplastic’ abnormality on initial or short term follow upor short term follow up

The estimated cumulative frequency of The estimated cumulative frequency of pancreatic cancer in this group is 5-40%pancreatic cancer in this group is 5-40%

EUS is sensitive but specificity is EUS is sensitive but specificity is problematicproblematic

Canto CGH 2004 and 2006, Levy CGH 2006

How does EUS/FNA compare How does EUS/FNA compare with CT or MRI for diagnosis of with CT or MRI for diagnosis of early cancers?early cancers?

EUS FNA

Cancer Benign Likelihood Ratio

Malignant 57/61 (93%) 0/41 (0%) > 9.7

Inconclusive 1/61 (2%) 7/41 (17%) 0.096 (0.01-0.8)

Negative 3/61 (5%) 34/41 (83%) 0.05 (0.02-.2)

EUS FNA of Pancreas Masses When CT FNA or ERCP Sampling are NegativeEUS FNA of Pancreas Masses When CT FNA or ERCP Sampling are Negative

Gress et al, Annals of Internal Medicine 2001

How does EUS/FNA compare How does EUS/FNA compare with CT or MRI for diagnosis of with CT or MRI for diagnosis of early cancers?early cancers?

Diagnostic yield in enriched Diagnostic yield in enriched screening cohortscreening cohort– EUS EUS 7 of 87 of 8– CT CT 5 of 85 of 8– ERCP ERCP 2 of 82 of 8

EUS FNA can show mucinous EUS FNA can show mucinous material and dysplasia which may material and dysplasia which may be helpfulbe helpful

Canto CGH 2004 and 2006, Levy CGH 2006

What is the risk of What is the risk of complications with EUS and complications with EUS and EUS-FNA?EUS-FNA?

EUS similar to EUS similar to EGDEGD

1-2% incidence 1-2% incidence of pancreatitis of pancreatitis with FNAwith FNA

Post EUS FNA Pancreatitis/Duct Leak

Post EUS FNA Pancreatitis/Duct Leak

Post EUS FNA Pancreatitis/Duct Leak

Can EUS potentially be used for Can EUS potentially be used for detecting and diagnosing detecting and diagnosing pancreatic cancer in enriched pancreatic cancer in enriched population subsets?population subsets?

YesYes– IPMN is a common precursorIPMN is a common precursor– Subtle abnormalities may not be Subtle abnormalities may not be

uniformly recognized (hypoechoic uniformly recognized (hypoechoic foci, inhomogeneity)foci, inhomogeneity)

– Specificity issues remainSpecificity issues remain

Role of EUS in diagnosing Role of EUS in diagnosing cancer in patients with cancer in patients with subtle/non-specific findings subtle/non-specific findings suggestive of cancer on CT suggestive of cancer on CT scan/MRI?scan/MRI?

Fletcher 2003 Radiology

Accuracy P

Index CT .64

TpMDCT .96 .004

GdMRI .92 .04

EUS .96 .008

Tumor Detection in Patients with Suspected Pancreas CancerTumor Detection in Patients with Suspected Pancreas Cancer

SummarySummary

Are there workforce issues if screening Are there workforce issues if screening became generally accepted?became generally accepted?– No reimbursementNo reimbursement– Probably the most difficult EUS exam to Probably the most difficult EUS exam to

performperform Is there a realistic mechanism for quality Is there a realistic mechanism for quality

control?control?– US interobserver agreement varies depending US interobserver agreement varies depending

on severity of abnormalityon severity of abnormality– Readily available gold standard is availableReadily available gold standard is available

Questions to panelQuestions to panel

What is the current status of What is the current status of pancreas cancer screening or early pancreas cancer screening or early diagnosis today? diagnosis today? – Who should be screened?Who should be screened?

How much should the population be enriched How much should the population be enriched before testing for pancreatic cancer before testing for pancreatic cancer becomes justifiable?becomes justifiable?

– How often? What age should we How often? What age should we start/stop? start/stop?

– What modality?What modality?

Questions to panelQuestions to panel

What is the future of pancreas What is the future of pancreas cancer screening or early cancer screening or early diagnosis?diagnosis?– EUSEUS– Biomarkers Biomarkers

Where should we look (serum, plasma, Where should we look (serum, plasma, pancreatic fluid, urine)?pancreatic fluid, urine)?

– Functional or molecular imagingFunctional or molecular imaging Can we “see” PanIns?Can we “see” PanIns?

Questions to panelQuestions to panel

Will stage migration/early Will stage migration/early detection lead to better detection lead to better outcomes?outcomes?

What are the impediments to What are the impediments to screening and how do we screening and how do we overcome them?overcome them?

Is there a role for prophylactic Is there a role for prophylactic pancreatectomy?pancreatectomy?