Colorectal cancer chemoprevention Silvia Zanardi, MD Recent Advances in the Management of Colorectal cancer May 6-7, 2005 Vilnius, Lithuania Division of

Colorectal cancer chemoprevention

Silvia Zanardi, MD

Colorectal cancer chemoprevention

Silvia Zanardi, MD

Recent Advances in the Management of Colorectal cancer

May 6-7, 2005 Vilnius, Lithuania

Recent Advances in the Management of Colorectal cancer

May 6-7, 2005 Vilnius, Lithuania

Division of Medical and Preventive Oncology

E.O. Ospedali Galliera Genoa, Italy

Division of Medical and Preventive Oncology

E.O. Ospedali Galliera Genoa, Italy

Human carcinogenesis is a multiyear process

Human carcinogenesis is a multiyear process

Clin Cancer Res 2002; 8:314

IEN

CANCERCANCER

Late, nonobligate stage of

CARCINOGENESICARCINOGENESISSChronic process that

provides time and targets for

CHEMOPREVENTIONCHEMOPREVENTION

Definition of cancer chemopreventionDefinition of cancer chemoprevention

Use of natural or synthetic agents to arrest or reverse the carcinogenesis process before the onset of the clinical disease

Mike Sporn, Cancer Res, 1976

ChemopreventionChemoprevention==

ChemopreventionChemoprevention==

Chemotherapy of dysplasia or

intraepithelial neoplasia

Adenoma-carcinoma Adenoma-carcinoma sequencesequenceAdenoma-carcinoma Adenoma-carcinoma sequencesequence

Colon carcinogenesis and the effects of chemoprevention agents

NEJM 2000; 342:1960

Estrogen+MPAEstrogen+MPA

Preventive agents Preventive agents Preventive agents Preventive agents

Folic Acid

Calcium–Vit.D3

Aspirin Anti COX-2

DFMO

Diet-MicronutrientsDiet-Micronutrients

NO-Aspirin

SulindacSulindacSulindac

Mechanisms of action of NSAIDs and selective COX-2 inhibitors.

NEJM 2000;

342:1960

Cancer 2000; 89:2637

Cancer 12/17 (71%)

Adenoma 6/7 (86%)

Normal adjacent mucosa 3/15 (20%)

Normal distant mucosa 0/6 (-)

COX-2 expression in COX-2 expression in colonic mucosacolonic mucosaCOX-2 expression in COX-2 expression in colonic mucosacolonic mucosa

Self selected Aspirin use

Randomization1982

End ofRandomized

Treatment 1988

End of follow-up

1995

Aspirin vs. placebo

Colorectal cancer incidence

71% ASA regularly

29% no medication

Male physicians22071

age 40-84

325 mg ASAVs.

Placebo

RR (95% CI)1.03 (0.83-1.28)

Aspirin use and colorectal cancerAspirin use and colorectal cancerPhysicians’ Health StudyPhysicians’ Health Study Aspirin use and colorectal cancerAspirin use and colorectal cancerPhysicians’ Health StudyPhysicians’ Health Study

Sturmer et Al., Ann Int Med 1998; 128:713

Baron et Al., N Engl J Med 2003; 348:891

0.7 ± 0.50.7 ± 0.50.7 ± 0.5Estimated diameter of largest qualifying adenoma – cm

1.6 ± 1.01.6 ± 1.01.6 ± 1.0 No. of adenomas on examinations qualifying for study entry

127 (34.1)108 (28.6)124 (33.3)Qualified for study with adenoma 1 cm – no. (%)

171 (46.1)177 (47.1)166 (44.9)Qualified for study with history of 1 adenoma – no. (%)

2.4 ± 2.42.2 ± 2.02.4 ± 2.2No. of reported adenomas before randomization

125 (33.6)111 (29.4)105 (28.2)Colorectal cancer in first-degree relative – no. (%)

235 (63.2)244 (64.7)233 (62.6)Male sex – no. (%)

57.7 ± 9.157.3 ± 9.957.4 ± 9.9Age – yr

325 mg of aspirin(n = 372)


Placebo(n = 372)Characteristics

ASA to prevent CR adenomaASA to prevent CR adenomaBase-line characteristics of the patientsBase-line characteristics of the patientsASA to prevent CR adenomaASA to prevent CR adenomaBase-line characteristics of the patientsBase-line characteristics of the patients

ASA and sporadic colon adenomaASA and sporadic colon adenomaASA and sporadic colon adenomaASA and sporadic colon adenoma

1 polyp P #

Subjects Agent Results

1121 subjects with recent adenoma

Aspirin 81* mg Aspirin 325**mg Placebo

38 %45%47%

0.04

RR * 0.81 (95% CI 0.69-0.96) ** 0.96 (95% CI 0.81-1.13)

Baron et Al., N Engl J M 2003; 348: 891

# treatment vs. placebo

Baron et Al., N Engl J Med 2003; 348:891

0.24

0.65

0.06

0.76

0.24

0.71

0.21

0.20

0.93

P Value

262 Genitourinary

423 Gastrointestinal

Serious bleeding

520Stroke

534Coronary revascularization

521Myocardial infarction

321Colorectal cancer

9146Noncolorectal cancer

576144Hospitalization

433Death



Placebo(n = 372)Adverse event

ASA to prevent CR adenomaASA to prevent CR adenomaIncidence of serious adverse events Incidence of serious adverse events ASA to prevent CR adenomaASA to prevent CR adenomaIncidence of serious adverse events Incidence of serious adverse events

239 (38)118 (37)121 (38) Dukes’ B2 or C

396 (62)200 (63)196 (62) Dukes’ A or B1

Cancer stage

180 (28)88 (28)92 (29) 70 yr

208 (33)

152 (24)

87 (14)

8 (1)

303 (48)

332 (52)

Total(n = 635)

4 (1)4 (1) 39 yr

150 (47)153 (48) Female

75 (24)77 (24) 50-59 yr

168 (53)164 (52) Male

105 (33)103 (32) 60-69 yr

46 (14)41 (13) 40-49 yr

Age

Sex

Placebo(n = 318)

Aspirin(n = 317)Characteristic

Sandler et Al., N Engl J Med 2003; 348:883

ASA to prevent CR adenoma in prior ASA to prevent CR adenoma in prior CRCCRCBase-line characteristics of the patientsBase-line characteristics of the patients

ASA to prevent CR adenoma in prior ASA to prevent CR adenoma in prior CRCCRCBase-line characteristics of the patientsBase-line characteristics of the patients

635 subjects with prior CCR

Aspirin 325 mgPlacebo

17%27% 0.004

RR 0.65 (95% CI 0.46-0.91)

ASA to prevent CR adenoma ASA to prevent CR adenoma in prior CRCin prior CRCASA to prevent CR adenoma ASA to prevent CR adenoma in prior CRCin prior CRC

Subjects Treatment Results

1 polyp P


ASA to prevent CR adenoma in prior CRCASA to prevent CR adenoma in prior CRCASA to prevent CR adenoma in prior CRCASA to prevent CR adenoma in prior CRC

Kaplan-Meier estimates of the time to a first adenoma.


Lysine ASA and prevention of CR Lysine ASA and prevention of CR adenomaadenoma

Lysine ASA and prevention of CR Lysine ASA and prevention of CR adenomaadenoma

Summary of the APACC TrialAPACC Trial design and first year of follow-up.

291 potentially eligible subjects asked to take part in 4-week run-in phase291 potentially eligible subjects asked to take part in 4-week run-in phase

272 eligible subjects randomized272 eligible subjects randomized

238 completed the year one colonoscopy


Benamouzig et Al., Gastroenterology 2003; 125:328

140 assigned to the Lysine acetylsalicylate LAS group140 assigned to the Lysine acetylsalicylate LAS group

132 assigned to the placebo group

132 assigned to the placebo group

73 in the LAS 160 mg/day group










Lysine ASA and prevention of CR adenomaLysine ASA and prevention of CR adenomaRisk of recurrent adenomas associated with treatmentRisk of recurrent adenomas associated with treatmentLysine ASA and prevention of CR adenomaLysine ASA and prevention of CR adenomaRisk of recurrent adenomas associated with treatmentRisk of recurrent adenomas associated with treatment

Benamouzig et Al., Gastroenterology 2003; 125:328

Adenomas in the 238 patients who completed the year 1 colonoscopy of the 272 randomized

Aspirin(n = 126)

Placebo(n = 112)

Crude relative risk (95% CI)

P

1 38 (30.2%) 46 (41.1%) 0.73 (0.52–1.04) 0.08

3 4 (3.2%) 12 (10.7%) 0.30 (0.10–0.89) 0.03

At least one >5 mm 13 (10.3%) 26 (23.2%) 0.44 (0.24–0.82) 0.01

At least one >10 mm 1 (0.8%) 7 (6.2%) 0.13 (0.02–1.02) 0.05

At least one recurrent tubulovillous or villous 8 (6.4%) 9 (8.0%) 0.79 (0.32–1.98) 0.61

At least one with high-grade dysplasia 0 (0.0%) 3 (2.7%) 0.0 0.10

At least one advanced adenoma 8 (6.4%) 13 (11.6%) 0.55 (0.24–1.27) 0.16

Mean number (±SD) of recurrent adenomas 0.45 (±0.15) 0.86 (±0.30) 0.01

Mean (±SD) adenomatous polyp burden 1.55 (±0.53) 4.03 (±1.46) 0.001

Placebo ASA 81 mg

ASA 650 mgASA 325 mg

PG E2 levels (pg/g protein) in relation to aspirin dose

Sample et Al., CEB&P 2002; 11:275

August 2003 • Volume 125 • Number 2

EditorialWill an aspirin a day keep the endoscope away?

EditorialWill an aspirin a day keep the endoscope away?Raymond N. DuboisDepartments of Medicine, Cell-Developmental Biology, and Cancer BiologyThe Vanderbilt-Ingram Cancer CenterVanderbilt University Medical CenterNashville, Tennessee, USA

http://www2.gastrojournal.org/scripts/om.dll/serve?action=searchDB&searchDBFor=home&id=gast

COX-2 COX-2 selectivityselectivity

of NSAIDsof NSAIDs

COX-2 COX-2 selectivityselectivity

of NSAIDsof NSAIDs

5-to 50-fold COX-2 selective

<5fold COX-2 selective

> 50-fold COX-2 selective

PNAS 1999; 96:7563

FAP: secondary preventionFAP: secondary preventionFAP: secondary preventionFAP: secondary prevention

Mean (± SE) % change from baseline in polyp number number in 22 subjects treated with 150 mg bid or placebo for 9 months

Giardiello et Al., N Engl J Med 1993; 328:1313

FAP: secondary preventionFAP: secondary preventionFAP: secondary preventionFAP: secondary prevention

Mean (± SE) % change from baseline in polyp sizesize.Giardiello et Al., N Engl J Med 1993; 328:1313

Cruz-Correa et Al., Gastroenterology 2002;122:641

FAP: secondary prevention (n=12)FAP: secondary prevention (n=12)

Incidence and toxicity grade of adverse reactionsIncidence and toxicity grade of adverse reactions

FAP: secondary prevention (n=12)FAP: secondary prevention (n=12)

Incidence and toxicity grade of adverse reactionsIncidence and toxicity grade of adverse reactions

n (%)Adverse reactionToxicity

grade

Gastrointestinal erosions (IR) 6 (50) G2

Gastrointestinal – other (abdominal bloating) 1 (8) G2

Hepatic hyperbilirubinemia 2 (17) G2

Pulmonary – other (bronchitis) 2 (17) G1

Syndromes – other (flu-like) 2 (17) G1–2

Auditory/hearing – other (tinnitus) 1 (8) G1

Metabolic/laboratory (hypokalemia) 1 (8) G1

Neurologic (dizziness) 1 (8) G1

Steinbach et Al,. N Engl J Med 2000; 342:1946

Percent change from base line in the mean number of polyps Percent change from base line in the mean number of polyps and colorectal polyp burden in patients with FAP treated for and colorectal polyp burden in patients with FAP treated for

six monthssix months

Percent change from base line in the mean number of polyps Percent change from base line in the mean number of polyps and colorectal polyp burden in patients with FAP treated for and colorectal polyp burden in patients with FAP treated for

six monthssix months

-22.5 ±26.0-3.4 ± 35.0+3.1 ± 31.1 Percent change in no. of rectal polyps

0.0030.33 P value

0.010.52 P value

0.0010.09 P value

-30.7 ± 25.7-14.6 ± 31.7

-4.9 ± 17.3Percent change in colorectal polyp burden

-28.0 ± 24.0-11.9 ± 30.3

-4.5 ± 16.4Percent change in no. of colorectal polyps

400 mg of celecoxibcelecoxib twice daily

(n = 30)

100 mg of celecoxib celecoxib twice daily

(n = 32)Placebo(n = 15)Variable

Change in adenomatous Ki-67 after 6 months of 400 mg (x) and 100 mg (+) celecoxib twice daily or placebo (o)

Sinicrope et Al., CEB&P 2004; 13:920

Mean % of change from baseline in the number of polyps. Polyp number at 9 months: rofecoxib, decreased by 6.8%; placebo increased by 3.1% (P = 0.004).

Higuchi et Al., Clin Cancer Res 2003; 9:4756

Month

% C

han

ge f

rom

bas

elin

e

Rofecoxib

n=9 n=12

Mean % of change from base line in the size of polyps. At 9 months: -16.2% in the rofecoxib group versus 1.5% in the placebo group (P < 0.001).

Higuchi et Al., Clin Cancer Res 2003; 9:4756

Month

% C

han

ge f

rom

bas

elin

e

Rofecoxib

n=9 n=12

Bresalier et Al., N Engl J Med 2005: 352:1092

CV events associated with Rofecoxib (APPROVe Trial)


CV events associated with Celecoxib (APC Trial)

CV events associated with Celecoxib (APC Trial)

Solomon et Al., N Engl J Med 2005: 352:1071

Levin B, JNCI 2003; 95: 697

Time line of evaluation of surrogate Time line of evaluation of surrogate endpoints associated with chemopreventive endpoints associated with chemopreventive

studiesstudies

Time line of evaluation of surrogate Time line of evaluation of surrogate endpoints associated with chemopreventive endpoints associated with chemopreventive

studiesstudies

Easy identification of at-risk population

screening genetic-environmental interactions

Availability of active agents ASA, other NSAIDs

Intermediate biomarkers adenomatous polyp other surrogate biomarkers (ACF, PGE2

expression, Ki-67, apoptosis)

CRC chemoprevention promising strategy

CRC chemoprevention promising strategy

Conclusions IIConclusions II ASA reduces the risk of recurrence of

adenoma in phase III trials

Coxibs and sulindac reduce number and size of adenomas in subjects with phenotypically manifested FAP

Risks associated with the long-term use of Coxibs need to be weighed against any potential benefits of these drugd in preventing CRC

Mean total, gastric, and duodenal endoscopic damage score (erosive and hemorrhagic lesions) after 7 days of treatment (n = 8 per group)

Fiorucci et Al., Gastroenterology 2003: 124:600

Gastrointestinal safety of NO-Aspirin (NCX-4016)Gastrointestinal safety of NO-Aspirin (NCX-4016)

00 Tubulovillous or villous

11 (55)9 (43) Tubular

6 (30)3 (14) 1-10

9 (45)12 (57) 0

7 (35)4 (19)Large adenomas ( 2.5 mm)

No. of adenomas

Histologic type of adenoma

5 (25)6 (29) 11

11 (55)9 (43) 1

no. (%)

Placebo group

(n =20)

Sulindac group

(n =21)Characteristic

FAP: primary preventionFAP: primary preventionCharacteristics of adenomatous polyps at the end of Characteristics of adenomatous polyps at the end of

treatmenttreatment

FAP: primary preventionFAP: primary preventionCharacteristics of adenomatous polyps at the end of Characteristics of adenomatous polyps at the end of

treatmenttreatment

Giardiello et Al., N Engl J Med 2002; 346:1054

Too cheap!Too cheap!

Why? Why?

DifficultDifficult

Baron et al., N Engl J Med 2003; 348:891

32.8 ± 3.732.5 ± 3.432.9 ± 4.2Duration of follow-up – mo

18 (5.1)12 (3.3)12 (3.3) Interim endoscopy

343 (96.6)357 (97.5)349 (96.1) Entire large-bowel mucosa well visualized

37 (10.4)24 (6.6)35 (9.6) Late follow-up examination

9 (2.5)10 (2.7)10 (2.8) Early follow-up examination

309 (87.0)332 (90.7)318 (87.6) Within specified interval

355366363 Total no. Evaluated

Follow-up examination at least 1 yr after randomization – no. (%)

01 (0.3)1 (0.3)Follow-up examination only in 1st yr after randomization – no. (%)

13 (3.5)7 (1.9)5 (1.3)No follow-up examination – no. (%)

4 (1.1)3 (0.8)3 (0.8)Died – no. (%)



Placebo(n = 372)Variable

ASA to prevent CR ASA to prevent CR adenomaadenomaFollow-up of patientsFollow-up of patients

ASA to prevent CR ASA to prevent CR adenomaadenomaFollow-up of patientsFollow-up of patients

ASA: dose-findingin 65 subjects

I: 24 hII: 14 dIII: 72 h after

IIIV: III/I

J Natl Cancer Inst 1997; 89:1152

Dose Dose

Cruz-Correa, Gastroenterology 2002; 122:641

FAP: secondary preventionFAP: secondary prevention

Long-term effect (63±31 mos) of sulindac on Long-term effect (63±31 mos) of sulindac on the number of rectal polyps in 12 subjectsthe number of rectal polyps in 12 subjects

FAP: secondary preventionFAP: secondary prevention

Long-term effect (63±31 mos) of sulindac on Long-term effect (63±31 mos) of sulindac on the number of rectal polyps in 12 subjectsthe number of rectal polyps in 12 subjects

Mean (SD) Range P value

Number of polyps

Baseline 28.9 (26.2) 7–80 —

12 months 6.8 (10.1) 0–28 76 0.002

Last follow-up 8.3 (14.5) 0–50 74 0.004

% % Reduction Reduction

from from baselinebaseline

Giardiello et Al., Gastroenterology 2004; 126:425

FAP: primary preventionFAP: primary preventionChange in PG levels in rectal mucosa of patients taking Change in PG levels in rectal mucosa of patients taking

sulindac who remained polyp free compared with patients sulindac who remained polyp free compared with patients who developed polypswho developed polyps

FAP: primary preventionFAP: primary preventionChange in PG levels in rectal mucosa of patients taking Change in PG levels in rectal mucosa of patients taking

sulindac who remained polyp free compared with patients sulindac who remained polyp free compared with patients who developed polypswho developed polyps

PGD2 58.4 ± 21.0 86.6 ± 81.2

0.023

PGE2 66.1 ± 23.1 102.4 ± 72.5

0.117

PGF2 76.5 ± 29.3 115.2 ± 65.5

0.082

TXB2 63.5 ± 28.0 138.1 ± 112.3

0.038

6KF1 70.2 ± 30.2 170.7 ± 150.5

0.035

aCalculated by t test.

Polyp-free (n = 11)

With polyps(n = 10) P valueaProstaglandi

n

Mean percentage of baseline value (± SD)

Steinbach et Al,. N Engl J Med 2000; 342:1946

FAP: secondary preventionFAP: secondary prevention FAP: secondary preventionFAP: secondary prevention

0.6537.6±29.434.8±28.144.7±36.5Polyp burden – mm

0.632.9±0.62.9±0.72.9±0.5Polyp size –mm

0.6612.3±8.211.5±8.515.5±13.4No. of polyps

18 (60)24 (75)10 (67) Colectomy

12 (40)8 (25)5 (33) Intact colon

0.45Surgical status – no. (%)

12 (40)15 (47)6 (40) Female

18 (60)17 (53)9 (60) Male

0.84Sex – no. (%)

0.04

P value

33.1 ±10.938.6±10.039.9±11.3Age – yr

400 mg celecoxib

twice daily(n = 30)

100 mg celecoxib twice daily

(n = 32)Placebo(n = 15)

Patients’ BaselineCharacteristics







CV events associated with Parecoxib and Valdecoxib after coronary by-pass graftingCV events associated with Parecoxib and

Valdecoxib after coronary by-pass grafting

0

0,2

0,4

0,6

0,8

1

1,2

1,4

Meta-analysis(Placebo)

23407

VIGOR(Rofecoxib)

4047

CLASS(Celecoxib)

3987No. of patients

An

nu

ali

zed

my

oc

ard

ial

infa

rcti

on

ra

te,

%

0.52

0.740.80

P = .04

P = .02

JAMA 2001; 286:954

Comparison of MI rates among subjects receiving placebo vs rofecoxib or celecoxibComparison of MI rates among subjects receiving placebo vs rofecoxib or celecoxib

Endoscopic score of gastric damage NO-releasing aspirin vs. aspirin COX-2 inhibitor

Endoscopic score of gastric damage NO-releasing aspirin vs. aspirin COX-2 inhibitor

PNAS 2003; 100:10937

Effect of aspirin on NCX-4016 on platelet aggregation

Gastroenterology 2003: 124:600

0

0,5

1

1,5

2

2,5

3

3,5

0 >0 to <5 5 to10 >10

Serum Estradiol Level, pmol/L

4-Year risk of breast cancer in the MORE trial

4-Year risk of breast cancer in the MORE trial

Placebo

Raloxifene

Bre

ast

Can

cer

Ris

k,

%

Cummings et al JAMA 2002

Documents

Colorectal cancer chemoprevention Silvia Zanardi, MD Recent Advances in the Management of Colorectal cancer May 6-7, 2005 Vilnius, Lithuania Division of