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