colorectal cancer chemoprevention silvia zanardi, md recent advances in the management of colorectal...
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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
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Human carcinogenesis is a multiyear process
Human carcinogenesis is a multiyear process
Clin Cancer Res 2002; 8:314
IEN
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CANCERCANCER
Late, nonobligate stage of
CARCINOGENESICARCINOGENESISSChronic process that
provides time and targets for
CHEMOPREVENTIONCHEMOPREVENTION
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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
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ChemopreventionChemoprevention==
ChemopreventionChemoprevention==
Chemotherapy of dysplasia or
intraepithelial neoplasia
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Adenoma-carcinoma Adenoma-carcinoma sequencesequenceAdenoma-carcinoma Adenoma-carcinoma sequencesequence
Colon carcinogenesis and the effects of chemoprevention agents
NEJM 2000; 342:1960
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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
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Mechanisms of action of NSAIDs and selective COX-2 inhibitors.
NEJM 2000;
342:1960
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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
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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
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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)
81 mg of aspirin(n = 377)
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
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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
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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
325 mg of aspirin(n = 372)
81 mg of aspirin(n = 377)
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
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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
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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
Sandler et Al., N Engl J Med 2003; 348:883
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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.
Sandler et Al., N Engl J Med 2003; 348:883
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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
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
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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Bresalier et Al., N Engl J Med 2005: 352:1092
CV events associated with Rofecoxib (APPROVe Trial)
CV events associated with Rofecoxib (APPROVe Trial)
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CV events associated with Celecoxib (APC Trial)
CV events associated with Celecoxib (APC Trial)
Solomon et Al., N Engl J Med 2005: 352:1071
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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
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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
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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
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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)
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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
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Too cheap!Too cheap!
Why? Why?
DifficultDifficult
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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. (%)
325 mg of aspirin(n = 372)
81 mg of aspirin(n = 377)
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
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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
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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
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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)
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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
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CV events associated with Rofecoxib (APPROVe Trial)
CV events associated with Rofecoxib (APPROVe Trial)
Bresalier et Al., N Engl J Med 2005: 352:1092
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CV events associated with Rofecoxib (APPROVe Trial)
CV events associated with Rofecoxib (APPROVe Trial)
Bresalier et Al., N Engl J Med 2005: 352:1092
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CV events associated with Parecoxib and Valdecoxib after coronary by-pass graftingCV events associated with Parecoxib and
Valdecoxib after coronary by-pass grafting
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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
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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
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Effect of aspirin on NCX-4016 on platelet aggregation
Gastroenterology 2003: 124:600
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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