Colorectal cancer chemoprevention Silvia Zanardi, MD 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

Human carcinogenesis is a multiyear process Clin Cancer Res 2002; 8:314 IEN

CANCER Late, nonobligate stage of CARCINOGENESIS Chronic process that provides time and targets for CHEMOPREVENTION

Biological approaches to preventing cancer development CA Ca J Clin 2004; 54:150

Definition 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

Chemoprevention = Chemotherapy of dysplasia or intraepithelial neoplasia

Adenoma-carcinoma sequence Colon carcinogenesis and the effects of chemoprevention agents NEJM 2000; 342:1960

Estrogen+MPA Preventive agents Folic Acid Calcium–Vit. D3 Aspirin Anti COX-2 DFMO Diet-Micronutrients NO-Aspirin Sulindac

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 colonic mucosa

Self selected Aspirin use Randomization 1982 End of Randomized Treatment 1988 End of follow-up 1995 Aspirin vs. placebo Colorectal cancer incidence 71% ASA regularly 29% no medication Male physicians age mg ASA Vs. Placebo RR (95% CI) 1.03 ( ) Aspirin use and colorectal cancer Physicians’ Health Study Aspirin use and colorectal cancer Physicians’ Health Study Sturmer et Al., Ann Int Med 1998; 128:713

Baron et Al., N Engl J Med 2003; 348: ± 0.5 Estimated diameter of largest qualifying adenoma – cm 1.6 ± 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 ± ± ± 2.2No. 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 ± ± ± 9.9Age – yr 325 mg of aspirin (n = 372) 81 mg of aspirin (n = 377) Placebo (n = 372)Characteristics ASA to prevent CR adenoma Base-line characteristics of the patients ASA to prevent CR adenoma Base-line characteristics of the patients

ASA and sporadic colon adenoma  1 polyp P # SubjectsAgent Results 1121 subjects with recent adenoma Aspirin 81* mg Aspirin 325**mg Placebo 38 % 45% 47% 0.04 RR * 0.81 (95% CI ) ** 0.96 (95% CI ) Baron et Al., N Engl J M 2003; 348: 891 # treatment vs. placebo

Baron et Al., N Engl J Med 2003; 348: P Value 262 Genitourinary 423 Gastrointestinal Serious bleeding 520Stroke 534Coronary revascularization 521Myocardial infarction 321Colorectal cancer 9146Noncolorectal cancer Hospitalization 433Death 325 mg of aspirin (n = 372) 81 mg of aspirin (n = 377) Placebo (n = 372)Adverse event ASA to prevent CR adenoma Incidence of serious adverse events ASA to prevent CR adenoma 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)  39 yr 150 (47)153 (48) Female 75 (24)77 (24) yr 168 (53)164 (52) Male 105 (33)103 (32) yr 46 (14)41 (13) 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 CRC Base-line characteristics of the patients ASA to prevent CR adenoma in prior CRC Base-line characteristics of the patients

635 subjects with prior CCR Aspirin 325 mg Placebo 17% 27% RR 0.65 (95% CI ) ASA to prevent CR adenoma in prior CRC ASA to prevent CR adenoma in prior CRC SubjectsTreatment Results  1 polyp P Sandler et Al., N Engl J Med 2003; 348:883

ASA to prevent CR adenoma in prior CRC Kaplan-Meier estimates of the time to a first adenoma. Sandler et Al., N Engl J Med 2003; 348:883

Lysine ASA and prevention of CR adenoma APACC Trial Summary of the APACC Trial design and first year of follow-up. 291 potentially eligible subjects asked to take part in 4-week run-in phase 272 eligible subjects randomized 238 completed the year one colonoscopy 238 completed the year one colonoscopy Benamouzig et Al., Gastroenterology 2003; 125: assigned to the Lysine acetylsalicylate LAS group 132 assigned to the placebo group 73 in the LAS 160 mg/day group 73 in the LAS 160 mg/day group 67 in the LAS 300 mg/day group 67 in the LAS 300 mg/day group 60 completed the year one colonoscopy 60 completed the year one colonoscopy 66 completed the year one colonoscopy 66 completed the year one colonoscopy 112 completed the year one colonoscopy 112 completed the year one colonoscopy

Lysine ASA and prevention of CR adenoma Risk of recurrent adenomas associated with treatment Lysine ASA and prevention of CR adenoma Risk 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 1 38 (30.2%)46 (41.1%) 0.73 (0.52–1.04)0.08  3 3 4 (3.2%)12 (10.7%) 0.30 (0.10–0.89)0.03 At least one >5 mm13 (10.3%)26 (23.2%) 0.44 (0.24–0.82)0.01 At least one >10 mm1 (0.8%)7 (6.2%) 0.13 (0.02–1.02)0.05 At least one recurrent tubulovillous or villous8 (6.4%)9 (8.0%) 0.79 (0.32–1.98)0.61 At least one with high-grade dysplasia0 (0.0%)3 (2.7%) At least one advanced adenoma8 (6.4%)13 (11.6%) 0.55 (0.24–1.27)0.16 Mean number (±SD) of recurrent adenomas0.45 (±0.15)0.86 (±0.30) 0.01 Mean (±SD) adenomatous polyp burden1.55 (±0.53)4.03 (±1.46) 0.001

Placebo ASA 81 mg ASA 650 mg ASA 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 Editorial Will an aspirin a day keep the endoscope away? Raymond N. Dubois Departments of Medicine, Cell-Developmental Biology, and Cancer Biology The Vanderbilt-Ingram Cancer Center Vanderbilt University Medical Center Nashville, Tennessee, USA

COX-2 selectivity of NSAIDs COX-2 selectivity of NSAIDs 5-to 50-fold COX-2 selective <5fold COX-2 selective > 50-fold COX-2 selective PNAS 1999; 96:7563

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

Cruz-Correa et Al., Gastroenterology 2002;122:641 FAP: secondary prevention (n=12) Incidence and toxicity grade of adverse reactions FAP: secondary prevention (n=12) Incidence and toxicity grade of adverse reactions n (%)Adverse reaction Toxicity grade Gastrointestinal erosions (IR)6 (50)G2 Gastrointestinal – other (abdominal bloating)1 (8)G2 Hepatic hyperbilirubinemia2 (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 and colorectal polyp burden in patients with FAP treated for six months ± ± ± 31.1Percent change in no. of rectal polyps P value P value P value ± ± ± 17.3Percent change in colorectal polyp burden ± ± ± 16.4Percent change in no. of colorectal polyps celecoxib 400 mg of celecoxib twice daily (n = 30) celecoxib 100 mg of 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 % Change from baseline 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 % Change from baseline 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) Solomon et Al., N Engl J Med 2005: 352:1071

Levin B, JNCI 2003; 95: 697 Time line of evaluation of surrogate endpoints associated with chemopreventive studies

 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

Conclusions 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)

00 Tubulovillous or villous 11 (55)9 (43) Tubular 6 (30)3 (14) (45)12 (57) 0 7 (35)4 (19) Large adenomas (  2.5 mm) No. of adenomas Histologic type of adenoma 5 (25)6 (29)  (55)9 (43)  1 no. (%) Placebo group (n =20) Sulindac group (n =21)Characteristic FAP: primary prevention Characteristics of adenomatous polyps at the end of treatment FAP: primary prevention Characteristics of adenomatous polyps at the end of treatment Giardiello et Al., N Engl J Med 2002; 346:1054

Too cheap! Why? Difficult

Baron et al., N Engl J Med 2003; 348: ± ± ± 4.2Duration of follow-up – mo 18 (5.1)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 Total no. Evaluated Follow-up examination at least 1 yr after randomization – no. (%) 01 (0.3) Follow-up examination only in 1 st yr after randomization – no. (%) 13 (3.5)7 (1.9)5 (1.3)No follow-up examination – no. (%) 4 (1.1)3 (0.8) Died – no. (%) 325 mg of aspirin (n = 372) 81 mg of aspirin (n = 377) Placebo (n = 372)Variable ASA to prevent CR adenoma Follow-up of patients ASA to prevent CR adenoma Follow-up of patients

ASA: dose-finding in 65 subjects I: 24 h II: 14 d III: 72 h after II IV: III/I J Natl Cancer Inst 1997; 89:1152 Dose Dose

Cruz-Correa, Gastroenterology 2002; 122:641 FAP: secondary prevention Long-term effect (63±31 mos) of sulindac on the number of rectal polyps in 12 subjects FAP: secondary prevention Long-term effect (63±31 mos) of sulindac on the number of rectal polyps in 12 subjects Mean (SD)Range P value Number of polyps Baseline28.9 (26.2)7–80— 12 months6.8 (10.1)0– Last follow-up8.3 (14.5)0– % Reduction from baseline

Giardiello et Al., Gastroenterology 2004; 126:425 FAP: primary prevention Change in PG levels in rectal mucosa of patients taking sulindac who remained polyp free compared with patients who developed polyps FAP: primary prevention Change in PG levels in rectal mucosa of patients taking sulindac who remained polyp free compared with patients who developed polyps PGD ± ± PGE ± ± PGF ± ± TXB ± ± KF ± ± a Calculated by t test. Polyp-free (n = 11) With polyps (n = 10) P value a Prostaglandin Mean percentage of baseline value (± SD)

Steinbach et Al,. N Engl J Med 2000; 342:1946 FAP: secondary prevention FAP: secondary prevention ± ± ±36.5Polyp burden – mm ±0.62.9±0.72.9±0.5Polyp size –mm ± ± ±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 ± ± ±11.3Age – yr 400 mg celecoxib twice daily (n = 30) 100 mg celecoxib twice daily (n = 32) Placebo (n = 15) Patients’ Baseline Characteristics

CV events associated with Rofecoxib (APPROVe Trial) Bresalier et Al., N Engl J Med 2005: 352:1092

CV events associated with Rofecoxib (APPROVe Trial) Bresalier et Al., N Engl J Med 2005: 352:1092

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

Meta-analysis (Placebo) VIGOR (Rofecoxib) 4047 CLASS (Celecoxib) 3987 No. of patients Annualized myocardial infarction rate, % P =.04 P =.02 JAMA 2001; 286:954 Comparison 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

Serum Estradiol Level, pmol/L 4-Year risk of breast cancer in the MORE trial Placebo Raloxifene Breast Cancer Risk, % Cummings et al JAMA 2002

Plasma IGF-I and breast cancer risk All Postmenopause top vs bottom quintile of IGF-I top vs bottom tertile of IGF-I* Premenopause any age Premenopause <50 yrs *adjusted for IGFBP-3 Hankinson SE et al, Lancet breast cancer cases/ 620 age-matched controls Time from blood collection to diagnosis: 28 months (1-57) RR=0.99 ( ) RR=0.85 ( ) RR=2.88 ( ) RR=7.28 ( )