Pancreatic cancermafservizi.edinf.com/CMS/images/stories/EGEUS_2007_ppt/...Apoptosis resistance...

Università degli Studidi Verona

Dipartimento di Scienze

Biomediche e ChirurgicheCattedra e U.O di Gastroenterologia

Italo Vantini

Torino 2007

Pancreatic cancer:biology, clinics

and therapeutic options:the clinician point of view

introductionintroduction� In Europe accounts for

10.4% of all GI cancers, and frequency is rising

� Pancreatic cancercontinues to pose anenormous challenge forclinicians and scientists

� It is one of most difficultcancer to treat

- out of all pancreatic cancer patients, less than 5%survives at 5 years

- 10-15% of pancreatic cancers can undergo potentiallycurative surgery (only) - no more than 15% of patients submitted to potentially

curative surgery survives at 5 years

Median survival (months)

0

2

4

6

8

10

12

14

16

metastatic advanced surgery

Prognosis of pancreatic cancerhas not changed during

last 20 years

However:On the biological ground

significant progresshas been made in:

• better knowledge of risk factors• understanding key molecular events

in carcinogenesis

• description of precursor lesions and improved knowledge of pre-malignant or

high risk ones, description of theirnatural history and strategies

Some improvement in the management ofpatients with pancreatic cancer or suspected cancer

can be realistically expected because of:

• Improvement in operative mortalityand morbility and development

of regional centers• Improvement in selection of patientsfor resection surgery and reduction inunnecessary or untimed resection• Improvements in detection and ofcharacterization of smaller lesions

• Introduction of adjuvant chemotherapyand combined strategies

On the clinical ground

Risk factors

Pancreatic cancer

KnowledgeClinical impact (?)

Identified risk factors of pancreatic cancer

Most frequent andclinically relevant

In terziary referralcenters

Commonly, age and smoking can be takeninto account in a probabilistic clinical approach

Increasing age

Age > 50:risk = x 20

Relation Relation betweenbetween smoking andsmoking andpancreaticpancreatic cancercancer in in variousvarious studiesstudies

Author country study type RR remarkssmok/non smok

95% CI

Smoking increases the Relative Risk for pancreatic cancerby a factor of 2.3

smoke

SmokeSmoke and and chronicchronic pancreatitispancreatitis-- relative relative riskrisk --

0

2

4

6

8

10

12

non-smokers

1-10 cig. 11-40 cig.

cigarettes/day

OR

chronicpancreatitiscancer without CP

Talamini et al, 2000

smoke

RiskRisk of of pancreaticpancreatic cancercancer in in chronicchronicpancreatitispancreatitis

3-4% of allpancretic cancers

Relative Relative riskrisk of of pancreaticpancreatic cancercancer in in smokerssmokersand and nonnon--smokerssmokers ((withoutwithout and and withwith pancreatitispancreatitis))

smoke

Any role

of alcohol ?

alcohol

SmallNegligeable or

marginal

Metabolites andcarcinogenetic agents

result into aninflammatory response

If long lasting,anti-oxidative molecules

are not sufficient andtoxic agents cancause additionaloxidative stress

At later stage, K-Rasmutation and PanINoccur as precursorsfor ductal carcinoma

Underlying chronic pancreatitis, diabetesor gene mutation accelerate this process

In first 2 yearssince onset of

new diabetes, therisk sharply

increasesbut remains 2 folds

later tooHowever, the

absolute incidenceof cancer is low

PC in newly diagnosed diabetes occurred in younger people. It may represent a marker for a risk group (?)

diabetes

InheritedInherited disordersdisorders associatedassociatedwithwith pancreaticpancreatic cancercancer and and recognizedrecognized or or

candidate candidate geneticgenetic changeschanges

(10% at least)

familialhereditary

High risk of cancerbut very rare

Precursors ofpancreatic malignancies

On a biological ground, modelsof carcinogenesis

On a clinical ground, a great opportunityfor proper selection of patients at risk

and for avoiding untimed and/or unnecessary surgery

Pancreatic Intraepithelial Neoplasia (PanIN)

Intraductal Papillary MucinousNeoplasia (IPMNs)

Mucinous Cystic Neoplasms (MCNs)

encompasses the three knownmorphologically distinct

precursors to invasive cancer

Morphologically identified precursorsof pancreatic cancer

MolecularMolecular biologybiology of of pancreaticpancreatic carcinomacarcinoma

Progression model for pancreatic cancerPancreatic Intraepithelial Neoplasia (PanIN)

� mutations – activation of protoncogens

� loss of tumor suppressors

� apoptosis resistance

� signalling overexpressions and activation of carcinogenesis pathway

Precursors of pancreatic cancer, molecular mechanism and factors associated

with cancerogenesis

Pathological and molecular features support that PanINrepresent a continuum of intraductal neoplastic

progression to ductal carcinoma

Unfortunately, PanIN have minimal clinical relevance

PancreaticPancreatic carcinogenesiscarcinogenesis –– gene gene keykeyfactorsfactors ((mutationmutation, , deletiondeletion))

Encoding proteinspromoting cell growth

Expressing proteinsthat halt cell

proliferation orrepairing errors

kRAS (mutation) (90%)

p16 (50-70%)

p53 (40-70%)

DPC 4 (30-50%)

Multiple genetic abnormalitiesDPC 4 almost always associated with p16 inactivation

Tumor suppressors

BRCA2(DNA repair)

inactivation

activation

inactivation

mutation

InactivationAbnormal expression

changesPancreatic cancer paradigma:accumulation of multistepgenetic alterations in the

development of pancreatic cancer

KK--RAS RAS activatingactivating mutationmutation

k-RAS A membrane GTP-binding protein� Growth-mediated signal transduction pathway

involved in cell– proliferation– survival– migration

Mutation of k-RAS in continuously activated(protein-bound sate) form stimulates, through

an aberrant RAS signalling, a moltitude of downstream signalling cascade

ApoptosisApoptosis resistanceresistance

Extrinsic pathway

Ligation of “deathreceptors”

through ligandins(or TRAIL)

DISCDeath Inducing

Signalling Complex

Caspase 8/10 ExecutionerCaspases 3/6/7

apoptosis

Intrinsic pathway (mitochondrium)

BH3bcl

mitochondrium

Cytochrome CApaf1

Caspase 9

cytosolcomplex

permeab.

proapoptoticprosurvival

factors

Which factors contribute toward the establishmentof an antiapoptotic program ?

k-RASactivates proapototic:-the ARF-p53 system- caspase 6 and Apaf-1

- EF2 genes*-*cell regulation and apoptosis

k-RASMutation

can alter thisfunction

ApoptosisApoptosis resistanceresistance

Extrinsic pathway

Ligation of “deathreceptors”

through ligandins(or TRAIL)

Activation of apoptosis

DISCDeath Inducing

Signalling Complex

Caspase 8/10 ExecutionerCaspases 3/6/7

apoptosis

Intrinsic pathway (mitochondrium)

BH3bcl

mitochondrium

Cytochrome CApaf1

Caspase 9

cytosolcomplex

permeab.

proapoptoticprosurvival

factors

In pancreatic cancer the apoptotic resistancework expecially at death-receptor,

mithocondrial and caspase-inhibitor levelsPancreatic cancer cells have evolved

multiple antiapoptotic strategies

overexpresssedinhibitors

ApoptosisApoptosis resistanceresistance

Extrinsic pathway

Ligation of “deathreceptors”

through ligandins(or TRAIL)

DISCDeath Inducing

Signalling Complex

Caspase 8/10 ExecutionerCaspases 3/6/7

apoptosis

Intrinsic pathway (mitochondrium)

BH3bcl

mitochondrium

Cytochrome CApaf1

Caspase 9

cytosolcomplex

permeab.

proapoptoticprosurvival

factors

Most of factors mediating the resitanceto apoptosis are regulated by the transcriptional

NF-kB that in PC is activated, counteractingapoptosis through antiapoptotic mechanisms ,

but also contributing to proliferation in cancer cells

BortezomibInhibitor of NF-kB

(phase I in pancreatic cancer)

Pancreatic Intraepithelial Neoplasia (PanIN)

Intraductal Papillary MucinousNeoplasia (IPMNs)

Mucinous Cystic Neoplasms (MCNs)

Morphologically identified precursorsof pancreatic cancer

119 patients

50%

3/20

Operated upon Follow-up

5/89 patients were then operated upon within 36months for growing of the lesion,

In two cases Border-line IPMN was found, but in no patient malignancy was detected

In all cases, symptoms and Ca 19/9 were absentand normal respectively

All the other patients remained asymptomatic

Out of the 89 non-operated

A few A few commentscomments fromfrom a a clinicianclinician

� Therefore, noticeable progresses have been madeon the behaviour following detection , but an“improvement” in the secondary prevention of pancreatic cancer should not be claimed up to date

� Virtually all cases of IPMNs , but also most of MCNs, are actually asymptomatic and markers are normal

� Lesions are detected by chance in over 90% of the cases by US or CT scan for compliants notconsistent withpancreatic disease , and in a substantial number of patientsUS or CT scan investigation should not have beenindicated by a methodologically correctclinician

Clinicalfeatures

Mostly aspecificQuite often too late

Intervals (days)between onset

of symptoms andthe first medical

treatment(median 75 days)

+ lag phaseNB: 58 days in case of jaundice

Proportional hazard model analysis of patient survival

“Best” prognosis:• symptom free patients• jaundice as onset

Worst prognosis:• back pain*• nausea• increased Ca 19/9

* frequently associated with increased Ca 19/9

A practical “criteria”

very high probabilityof non resectability

20-30% probabilityof resectability

Other clinical presentations

Acute pancreatitisis a neglected, butnot unfrequent mode of clinical presentation

(mainly in tertiary-care centers)

All the patients with idiopathic acute pancreatitis, particularly over 50s, should

be suspected for having pancreatic malignancy.Since this is usually small, survival rate in these

patients, provided that the lesion is identified,is higher (about 5-10%) than in other presentations

EnzymesHCO3

Steatorrhoeamotility, break

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80 90

Lipasi %

Fec

al f

at

g/2

4 h

Duodenal pH

HEAD

Biomarkersfor pancreatic cancer

• Ca 19/9 is the most widely (but often improperly) used• sensitivity 70-90%, and specificity 70-98%• It is increased in jaundice and in benign disease

(chronic pancreatitis) too• only 49% of small pancreatic cancer less than 2 cm

in diameter and resectable have elevated Ca 19/9• Ca 19/9 is useless in distinguishing neoplasm with invasive

potential, such as Mucinous cystic tumors and IPMNs ,from those with benign feature nevertheless

• It helps surgeon in decision making as prognostic factor (ifpositive), and to suspect early recurrence or remnantdisease after resection

Grace to the progresses in pancreatic tumor biologyand technology, novel serum markersareunder investigation to foster dentification

of patients with early pancreatic malignancy(CEACAM 1 ?)

Imaging

DIAGNOSIS

Surgical,adjuvant, and

supportive-palliativetherapy

Pancreatic cancer

SurgerySurgery

� Surgey should be confined in specializedcenters

� Pancretoduodenectomy with or withoutPP is the most appropriate procedure

� Extended radical resection should not beundertaken because of high mortality and reduced quality of life

� Arterial ad portal vein reconstructionshould be considered in exceptionalcircumstances only

EndoscopicEndoscopic stentingstenting

� Endoscopic biliary stenting should be used in malignant biliary obstruction

� Pre-operative endoscopic biliary stenting doesnot influence the surgical outcome, but can help the general management

� Metal stenting can be used in patients with welldefined parameter (e.g. locally advanced cancer> 3 cm), otherwise plastic stents are indicated

� Duodenal obstruction can be managed byendoscopic procedure

Do not use the stenting as a therapeutic optionin patients potentially cured by surgery

SupportiveSupportive therapytherapy and and symptomsymptom controlcontrol

� Pancreatic enzyme supplement if steatorrhoea� Pain control in advanced cancer (opiates,

antidepressant, neurolytic celiac plexus block in selected cases)

� Treatment of cancer cachexia– Thalidomide– Omega-3 enriched formulas and diet– Psycotropic drugs

� Prophylactic gastrojejunostomy in younger patientswith good health status

� Biliary stenting in advanced cancer

PancreaticPancreatic cancercancer

Can we reallyimprove

life expectance

today ?

time of follow up (months)

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0,0

Survival after resection of “resectable” cancers(n= 184)

1997- October 2004Surgical & Gastroenterological Department – University of Verona

Median survival: 21.4 months(95%CI: 18.2-24.6)

Courtesy of Prof. P. Pederzoli and C. Bassi

20%5 years

R0-R1:survival rate does not significantlydiffer, but R2 survival is lower

R0: 42.0 mesi (IC 95%:14.8-69.1)

p= 0.001

R1: 21.5 mesi (IC 95%:20.6-22.4)

R2: 9.8 mesi (IC 95%:6.7-12.9)

time of follow up (months)

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0,0

R2

R1

R0

P[R0*R1]=0,14 (n.s.)

P[R0*R2]=0,00001

P[R1*R2]=0,001

Courtesy of Prof. P. Pederzoli and C. Bassi

time of follow up (months)

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20-25%

Inadequate staging of patients !

(and/or aggressive biology ?)

Courtesy of Prof. P. Pederzoli and C. Bassi

Neoptolemos et alGut 2006; 55: 1598-1605

survival:

15 vs 55months

(log rank, p=0.0008)

70 patients R0 submitted to curative resection

Irrespective ofTNM, age, sex,

Presence of PanIN

ESPAC

Standard care for patients withresectable pancreatic cancer

should consist of curativesurgeryfollowed as soon as possible

by adjuvant systemicchemotherapy

5-FU23 vs. 12%

MetaMeta--Analysis of Randomised Adjuvant Analysis of Randomised Adjuvant Therapy Trials for Pancreatic CancerTherapy Trials for Pancreatic Cancer

Courtesy of Prof. P. Pederzoli and C. Bassi

Adjuvant chemotherapyshould be used in both

R0 and R1 cancers

MetaMeta--Analysis of Randomised Adjuvant Analysis of Randomised Adjuvant Therapy Trials for Pancreatic CancerTherapy Trials for Pancreatic Cancer

However, further datafor R1 patients

are needed

Courtesy of Prof. P. Pederzoli and C. Bassi

The Influence of Resection Margins and Treatment on The Influence of Resection Margins and Treatment on Survival for Patients with Pancreatic Cancer within a Survival for Patients with Pancreatic Cancer within a

MetaMeta--analysis of Randomized Controlled Trialsanalysis of Randomized Controlled TrialsG. G. ButturiniButturini et al. on behalf of the Pancreatic Cancer et al. on behalf of the Pancreatic Cancer

MetaMeta--analysis Group (in press)analysis Group (in press)

Conclusions

� Adjuvant chemotherapy but not chemoradiation should be the standard of care for patients with either R0 or R1 resections for pancreatic cancer.

� We need further studies on R1 chemoradiation (53 pts per group only!)

AdjuvantAdjuvant chemotherapychemotherapy((synthesissynthesis))

� 5-FU : most widely used� Gemcitabine: little gain vs. 5-FU, but better

tolerability

� Combination Gemcitabine– Gemcitabine + capecitabine (better vs, gemcitabine)– Gemcitabine + platinum agents

� Combination Gemcitabine– + erlotinib– + cetuximab– + bevacizumab

A 20% A 20% survivalsurvival rate, rate, ((or little bit more)or little bit more) butbut……..

� Cancer is small

� Stage of the disease is < R2 (resection should be

considered a wrong choiche)

� Resection margins belong to RO-R1 stage

� Recurrences are common and frequently “early”: adjuvant

chemotherapy is mandatory

� Neo-adjuvant chemotherapy for down-staging cancer

needs further investigation, but it my be used in selected

patients

In In conclusionconclusion� Nowadays pancreatic cancer remains a real challenge

� An interdisciplinary approach is strongly recommended

� Developments in cancer biology , technology, procedures, and improvement in selection and strategies is probablyleading to some improvement in prognosis and quality of life, reducing unnecessary and untimed treatments at least

� Late presentation remains the big problem , strongly limitingthe rate of patients candidate for curative approach, and primary prevention is unrealistic

� Improvements in our knowledge and management of some precursors , and of high risk groups may be one of the waysfor further, though up to date small, improvements in face of this killer disease !

Cenotafio diJohann George

Wirsung

Padova,Basilica del Santo,

Chiostro del Capitolo

1642

Padova: giardino dei semplici(orto botanico)

fine

Diapo diriserva

Expanding roleIn diagnosis and staging

PanIN

IPMNIt is not clinically detected

Pancreatic malignant tumors

Survival rates after resection for IPMNs

Symptoms and location of tumor

Back pain

others

P=0.034

%survival

Days since onset of symptoms

Diagnosis of pancreatic cancer

The use of contrast enhanced CT is the preferredmethod for non-invasive diagnosis and staging

Secretin-MRCP can be selectivelyused(e.g. whenthe description of pancreatic ductal system is crucial)

EUS should be used selectively, for better identifyingsmaller lesions and for differential diagnosis

ERCP with brushig should be made patientsUndergoing endoscopic stenting

Tissue sampling should be sought in all casesdeemed unresectable, and should avoided in

when resection is judged possible

In experienced hands, contrast enhancedUS gives excellent information

RelationshipRelationship betweenbetween pancreaticpancreatic ductductlenghtlenght and and pancreaticpancreatic secretionsecretion

HEAD

Pancreatology 2003; 3: 1-8

smoke

calories

(occupation)

geneticHowever, in a

substantial proportion ofcases, no risk factor is

actually detectable,except for age

CurrentlyCurrently suggestedsuggested strategystrategy forforIPMNsIPMNs: : surgicalsurgical decisiondecision

Main duct IPMN

Branch duct IPMN

Follow-up

(most cases)

alcohol

familialhereditary

FH = Familial History of diabetes

diabetes

>

Risk factors of pancreatic cancersummary

For smoking (and diet) can be made a primary prevention only

For heredity and chronic pancreatis this target is unrealistic up to date

Recent case-control study suggestsan interaction and potentiation

among risk factors

Increasing chances for early detectionand classification of smaller lesions

Increasing evidence for improvedcriteria of management

CEACAM1 expression inPanIN lesion

CEACAM1 is upregulatedin pancreatic cancer and

present in the serumIt is more sensitive in

differentiating cancer fromnormal controls and the

difference is improved bycombination with Ca 19/9

Its presence in PanIN lesionscandidates the marker for

detecting early cancer?

PancreaticPancreatic cancercancer

Early death, short survival�Inadequate, “optimistic” pre-

operative staging�Aggressive biology�Other factors ?

time of follow up (months)

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40-45%

Surgery plays a role, but …

Courtesy of Prof. P. Pederzoli and C. Bassi

time of follow up (months)

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15%

A balanced cocktail : good biology, “quite”correct indication and approach!

•Survival•Division•Invasion•Adhesion

32% 1-year survival

24% 1-year survival

-Survival-Proliferation- Resistanceto apoptosis

- NF.kBBortezomib