aspirin, nsaids and cox2- inhibitors in crc prevention · total polyp number / mouse ptgs2 genotype...
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Aspirin, NSAIDs and COX2-inhibitors in CRC prevention
Angel LanasService of Gastroenterology
University of ZaragozaZaragoza. Spain
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
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
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
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
COX inhibitors in the prevention of CRC and/or GI cancers: Body of Evidence
• Epidemiological studies• Animal studies• Randomized Clinical Trials
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
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
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
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
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
Celecoxib is a potent Preventive and Therapeutic Agentin the Min Mouse Model of Adenomatouse Polyposis
Jacoby et al. Cancer Res 2000
Prevention Treatment
Giardiello et al, 1993Giardiello et al, 1993
Sulindac in Familial Adenomatous PolyposisSulindac in Familial Adenomatous Polyposis
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.
• 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
Sandler et al. NEJM 2003
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
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
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
Bertganolli M et al. 2006
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
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
Solomon et al. NEJM 2005
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
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
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
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”
CRC Chemoprevention
• What’s next?
–Under Study: Folate
–Also: Vitamin D?
–Look for new agents:•NO-NSAIDs?
–“POLY- PILL”??
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
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