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Aspirin, NSAIDs and COX2-inhibitors in CRC prevention
Angel LanasService of Gastroenterology
University of ZaragozaZaragoza. Spain
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Molecular Basis of the adenoma-carcinoma sequence
NormalNormalEpitheliumEpithelium
SmallSmallAdenomaAdenoma
LargeLargeAdenomaAdenoma
LocallyLocallyinvasiveinvasive
CarcinomaCarcinomaMetastaticMetastaticCarcinomaCarcinoma
APC APC MutationMutation
KK--RasRasMutationMutation
P53 P53 MutationMutationLossLoss ofof 18q18q
DCCDCC
Gen(s) Gen(s) lossesatat chrchr. . 4
NM 23 deletion,...
COXCOX--2 2 overexpressionoverexpression
EnvironmentalEnvironmentalfactorsfactors
40%40% 8080--90%90%
A. Lanas 2000A. Lanas 2000
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PPARδ
gene gene transcriptiontranscriptiontranscriptiontranscription
SignalsSignals SignalsSignals
AUTOCRINEAUTOCRINEPARACRINEPARACRINE
Adapted from
Prescott and Fitzpatrick 2000
A. Lanas 2001A. Lanas 2001
GrowthDifferentiation
ApoptosisAngiogenesis
CoxCox--2 2 productsproducts
RXRLigandLigand
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COX-2
APOPTOSIS
Arachidonic Acid
PGE2
Fosslien E, Ann Clin Lab Sci 2000
MITOCHONDRIA
BCL2
LO
BAX
HOOC- NSAIDS
OXPHOS
IL-6
Haptoglobin
AngiogenesisMetastasis
COXIBSNSAIDS
(-)
(-)
(+) (-)
(+)Cytochrome C
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Mechanisms of action of NSAIDs and COX-2 inhibitors - Colon Cancer
COXCOX--dependentdependentMechanismsMechanisms
COXCOX--IndependentIndependentMechanismsMechanisms
PhospholPhospholíípidspids
AAAA
ProstaglandinsProstaglandins
ApoptosisApoptosis
ApoptosisApoptosis
ApoptosisApoptosis
COXCOX--11
COXCOX--22
ASA/ASA/SulindacSulindac
CoxibsCoxibs
SphingSphing//ceramideceramide
AngiogenesisAngiogenesis
NFNF--kBkBPPARPPARδδ
OthersOthers
StimulationStimulationInhibitionInhibition
ProliferationProliferationA. Lanas 2000A. Lanas 2000
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COX inhibitors in the prevention of CRC and/or GI cancers: Body of Evidence
• Epidemiological studies• Animal studies• Randomized Clinical Trials
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Estimated Relative Risk
Kune ‘88Rosenberg ‘91
Suh ‘93 (hombres)Suh ‘93 (mujeres)
Peleg ‘ 94Schreinemachers ‘94
Giovannucci ‘94Giovannucci ‘95
Paganini-Hill ‘89, ‘91, ‘95LaVecchia ‘97
Sturmer ‘98Neugut’ 98Bucher ‘99
Kune ‘88Peleg ‘ 94
Muscat ‘94 (mujeres)Muscat ‘94 (hombres)
Müller ‘94Pinczowski ‘94
Bansal ‘96Reeves ‘96
Rosenberg ‘98Smalley ’99Rahme ’03
0.250.77
0.38
0.65
0.32
0 1 2
0.84
0.64
0.45
0.700.49
0.60.5
0.240.54
0.08
0.7
0.32
0.740.68
0.561.5
1.07
0.47
NSAID use and Risk of CRC
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NSAID use and Risk of colonic adenomas
Greenberg ‘93Suh ‘93
Giovannucci ‘94Logan ‘93
Martinez ‘95Peleg ‘96
Sandler ’98Rahme ’03
0.52
0.61
0.49
0.65
0.36
0.31
0.56
0 1 2Estimated Relative Risk
0.41
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Coxib use and Risk of colorectal Neoplasia
NSAIDs
Celecoxib
Rofecoxib
AspirinAcetaminophen
0.47
0.73
0.64
0.85
0 1 2Estimated Relative Risk
0.78
Rhame et al. 2003
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Effects of mutating or inhibiting COX-2 on intestinal polyps in ApcΔ716 mice
800
700
600
500
400
300
200
100
0(+/+) (+/-) (-/-)
Total polyp number / mouse
Ptgs2Genotype
652
224
93
600
500
400
300
200
100
0 NoDrug-
control
MFTricyclic
(14 mg/kg)
MFTricyclic
(3.5 mg/kg)
Sulindac(12 mg/kg)
Total polyp number / mouse
424
161210
312
Oshima et al, Cell 1996; 87: 803
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Effect of rofecoxib on polyp numberin APCΔ716 mice
*In feed, based on an assumed ingestion of 5 g feed / day
Total number of polyps
0.0
50
100
150
200
250
300
350
Control (n = 6) Rofecoxib15 mg/kg/day*
(n = 6)
Rofecoxib5 mg/kg/day*
(n = 5)
Sulindac30 mg/kg/day*
(n = 5)
201 (63.4)
91 (30.7)
129 (18.6)
124(65.7)
Evans et al, Am J Gastroenterol 2000; 95:2533
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Celecoxib is a potent Preventive and Therapeutic Agentin the Min Mouse Model of Adenomatouse Polyposis
Jacoby et al. Cancer Res 2000
Prevention Treatment
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Giardiello et al, 1993Giardiello et al, 1993
Sulindac in Familial Adenomatous PolyposisSulindac in Familial Adenomatous Polyposis
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Celecoxib Reduces Polyp Burden (Sum of Polyp Diameters) in Patients with FAP
-4.9
-14.6 *
-30.7 †-35
-30
-25
-20
-15
-10
-5
0
Cha
nge
in p
olyp
bur
den
(%)
PlaceboCelecoxib 100 mg bidCelecoxib 400 mg bid
* P = 0.09 vs placebo; † P = 0.001 vs placebo.
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• Adjusted Risk Ratios
Aspirin All Adenomas Advanced*81 mg 0.83 (0.70-0.98) 0.58 (0.37-0.90)325 mg 0.95 (0.80-1.12) 0.83 (0.55-1.23)
*≥ 1 cm, tubulovillous, villous, CIS, Ca
Aspirin Polyp Prevention Study
Baron et al. NEJM 2003
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Sandler et al. NEJM 2003
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Aspirin Chemoprevention• French Study
– 272 subjects randomized – Sporadic adenoma, big or multiple– Lysin acetylsalicylate 160 mg, 300 mg– F/U colo 1 year and 4 years
Year 1 RR ~ 0.73;95% CI: 0.52-1.04; P = 0.08Year 1 RR ~ 0.73;
95% CI: 0.52-1.04; P = 0.08
•Benamouzig R et al. Gastro 2003
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COX-2 selective inhibitors in CRC prevention
• Good potential candidates:
– Most GI premalignant and malignant lesionsoverexpress COX-2
– Better GI safety profile than NSAIDs and ASA
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Effect of Rofecoxib on polyprecurrence –The Approve Trial
41
26 25
55
4032
0
20
40
60
80
100
OVERALL YEAR 0-1 YEAR 1-3
RofecoxibPlaceboRR: 0.75; 95% CI: 0.67RR: 0.75; 95% CI: 0.67--0.830.83
RR: 0.79 (0.63RR: 0.79 (0.63--0.93)0.93)
RR: 0.65 (0.57RR: 0.65 (0.57--0.83)0.83)
% % patientspatients withwith polyppolyp recurrencerecurrence
Baron et al. Gastroenterology 2006
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Bertganolli M et al. 2006
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Pre-SAP Trial
• Cumulative rate of ALL adenomas - year 3:– 33.6 % in the celecoxib group– 49.3 % in the placebo group– RR: 0.64 (95% CI, 0.56-0.75; P<0.001).
• Cumulative rate of Advanced Adenomas - year 3: – 5.3 % in the celecoxib group– 10.4 % in the placebo group– RR: 0.49 (95 %, 0.33 to 0.73; P<0.001)
N = 557 placebo groupN = 840 celecoxib group Arber N et al. NEJM 2006
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APPROVe Confirmed Thrombotic Endpoint
0 6 12 18 24 30 36
Month
0
2
4
6
8C
umul
ativ
e In
cide
nce(
%) w
ith 9
5% C
I
PlaceboRofecoxib 25mg
Kaplan-Meier Estimates (95% CI)
RR(95% CI): 1.96 (1.20, 3.19)*
* p<0.05
Patients at RiskPlacebo
Rofecoxib 25 mg1299 1192 1148 1079 1039 1002 4701287 1123 1050 986 935 898 411
0.48 cases vs 1.08 cases x 100 pat-year
Bresalier et al. NEJM 2005
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Solomon et al. NEJM 2005
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Prevention Needs to be Safe
• Example: Population of 100,000• 2 per 1000 cases/year
• Non-toxic: 0.1% hepatitis, 0.1% syncope• NonNon--toxic: 0.1% hepatitis, 0.1% syncopetoxic: 0.1% hepatitis, 0.1% syncope• In 5 years: - 500 cases
+ 500 hepatitis+ 500 syncopeNet: ???
• In 5 years: In 5 years: -- 500 cases 500 cases + 500 hepatitis+ 500 hepatitis+ 500 syncope+ 500 syncopeNet: ???Net: ???
• Effective agent: ↓ 50% of cases• Effective agent: ↓ 50% of cases
Taken from J Baron
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Prevention Needs to be Safe
Population of 100,000• Advanced adenoma (AA) recurrence:
190 per 1000 cases / 3 years
• In 3 years: - 4750 cases of AA+ 2400 ulcers and bleedings+ 1500 non fatal CV events
Net: ???
• In 3 years: In 3 years: -- 4750 cases of AA4750 cases of AA+ 2400 ulcers and bleedings+ 2400 ulcers and bleedings+ 1500 non fatal CV events+ 1500 non fatal CV events
Net: ???Net: ???
• Rofecoxib: ↓ 25% of advanced adenomas0.5% - year of CV events0.8% - year of PUBs
• Rofecoxib: ↓ 25% of advanced adenomas0.5% - year of CV events0.8% - year of PUBs
Lanas et al. 2007Baron et al. 2006Bresalier et al. 2005
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Where are we now?
•• HereditaryHereditary CRC CRC syndromessyndromes
• Chemoprevention in FAP patients? YES– Celecoxib 400 mg once a day or b.id.
• ONLY APPROVED DRUG FOR FAP– Sulindac 150 mg b.i.d.
– Long-term follow-up studies needed– Careful evaluation of risks and benefits
• Chemoprevention in HNPCC syndrome?– No data
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Where are we now?
•• SporadicSporadic CRC :CRC :
Chemoprevention in patients with colonic polyps?
– No role for NSAIDs– No role for COX-2 selective inhibitors
– Low-dose aspirin? ... “May be”
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CRC Chemoprevention
• What’s next?
–Under Study: Folate
–Also: Vitamin D?
–Look for new agents:•NO-NSAIDs?
–“POLY- PILL”??
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GI Chemoprevention
• Outside clinical trials and FAP, today there is no indication of chemoprevention therapy with NSAIDs, aspirin or coxibs in sporadic CRC.
• Aspirin alone or combined with nutrients most serious candidates
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Aspirin Polyp Prevention Study
• Medical EventsAspirin
Placebo 81 mg 325 mg pM.I. 1 2 4 0.42Stroke 0 2 5 0.06
Baron et al. NEJM 2003