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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)
847260483624120
cum
ulat
ive
surv
ival
rat
e
1,0
,8
,6
,4
,2
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)
847260483624120
cum
ulat
ive
surv
ival
rat
e1,0
,8
,6
,4
,2
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)
847260483624120
cum
ulat
ive
surv
iva
l rat
e
1,0
,8
,6
,4
,2
0,0
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)
847260483624120
cum
ulat
ive
surv
ival
rat
e
1,0
,8
,6
,4
,2
0,0
40-45%
Surgery plays a role, but …
Courtesy of Prof. P. Pederzoli and C. Bassi
time of follow up (months)
847260483624120
cum
ulat
ive
surv
ival
rat
e1,0
,8
,6
,4
,2
0,0
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