Colon Cancer
Chemoprevention
UWCCC Chemoprevention Program
And Mayo Clinic Chemoprevention Program
Spirit of Eagles
September 6, 2007
Howard Bailey, MD and Paul Limburg, MD, MPH
Colon Cancer
Chemoprevention
 Need/Rationale
 150,000 expected to be diagnosed with
colorectal cancer in 2007
 >50,000 expected to die from colorectal cancer
in 2007
Estimated new Cancer Cases for 2007
Jemal et al. CA Cancer J Clin 2007
Estimated Cancer Deaths for 2007
Jemal et al. CA Cancer J Clin 2007
Annual Age-adjusted Cancer Incidence Rates
Jemal et al. CA Cancer J Clin 2007
Annual Age-adjusted Death Rate Males
Jemal et al. CA Cancer J Clin 2007
Annual Age-adjusted Death Rate Females
Jemal et al. CA Cancer J Clin 2007
Incidence of Selected Cancers by Race/Ethnicity
Jemal et al. CA Cancer J Clin 2007
Death Rates for Cancers by Race/Ethnicity
Jemal et al. CA Cancer J Clin 2007
Colo-rectal Cancer Incidence
JNCI Stat Bite, 2006
Colon Cancer
• Above data implies while colorectal cancer
remains a significant health issue, it appears to be
lessening including for American Indians/Alaska
Natives.
• Cancer mortality, in general, is less in American
Indians/Alaska Natives than general population
165 compared to 201 per 100,000; however
mortality rates for Alaska Natives and Northern
Plains Tribes is higher, especially for colorectal,
lung, liver, stomach, gall bladder and kidney
cancers.
Mortality Rates
Selected IHS sites
Slattery, J Cancer Educ 2005
Colon Cancer in Indian Country
• Harwell et al. (Am J Prev Med 30:493, 2006)
– Age adjusted 6-yr cancer incidence rates in
Montana, 1991-96 and 1997-2002
– All cancers incidence rates higher in American
Indians than whites
– Colon cancer incidence twice as high in
American Indian males as white males
Colon Cancer Prevention
• For the US population it remains important
despite decreasing incidence and mortality
• This appears especially true for Northern
Plains Tribes and Alaska Natives
• Many ways to accomplish this through
lifestyle, screening, etc..
• Will focus on the potential of
chemoprevention of colon cancer
Chemoprevention of Cancer
 The study of carcinogenesis has led to the
current dogma that human
carcinogenesis is a multi-year process
 Example – normal colonic mucosa to
hyperplastic polyps to adenomatous polyps to
carcinoma may take 10-30 years
 Thus providing an opportunity to
intervene prior to accumulated mutations
or phenotypic changes
Candidate Agents
• COX-2 inhibitors, selective or nonselective
• Diet and Nutraceuticals
• Antioxidants/Vitamins
• Statins
• Difluoromethylornithine (DFMO)
• Others
Selective COX-2 Inhibitors
• Celecoxib: FDA approved for adenomatous
polyp prevention for individuals with
Familial Adenomatous Polyposis
– These data and retrospective data have led to
extensive study of COX-2 inhibitors for
sporadic adenomas as well
Selective COX-2 Inhibitors
FAP Trial (phase IIb)
• Phenotypic expression
of APC mutation (n=81)
• 3 arms; duration = 6 mo.
- celecoxib 100 mg bid
-
celecoxib 400 mg bid
placebo bid
• Change in polyp burden
Steinbach, et al. - N Engl J Med 2000;342:1946-52; Images from E. Hawk, NCI
Subject #5120
41 Polyps at Baseline
Images courtesy of Dr. E. Hawk, NCI
21 Polyps at Follow-Up
Change in Polyp Number
% Change from Baseline
80
60
40
20
0
-20
- 4.5
- 11.9
-28.0%*
-40
-60
-80
Placebo 100 mg BID 400 mg BID
(N=30)
(N=15)
(N=32)
* p< 0.05; Steinbach, et al. - N Engl J Med 2000;342:1946-52
Sporadic Adenomas
Phase III Trials
APC Trial
• Sporadic CRN (n=2,035)
• 91 participating sites
• Celecoxib 200 mg bid or
400 mg bid vs. placebo
• Rec. adenomas at 3 years
AdvancedAdenomas
Adenomas
Recurrent
Placebo bid
*p<0.0001
vs. placebo; Bertagnolli – NEJM 2006;355:873-84
Celecoxib200 mg bid
Celecoxib400 mg bid
Phase III Trials
PreSAP Trial (n=1,561)
• 107 participating sites
• Celecoxib 400 mg qd
vs. placebo
• Rec. adenomas at 3
years
RR=0.64 (0.56-0.75);
any
RR=0.49 (0.33-0.73);
adv.
APPROVe Trial
(n=2,587)
• 108 participating sites
• Rofecoxib 25 mg qd vs.
placebo
• Rec. adenomas at 3
years
RR=0.76 (0.69-0.83);
any
RR=0.70 (0.57-0.73);
N Engl J Med 2006;355:885-95 and Gastroenterol 2006; epub
adv.
Cardiovascular Toxicity
Celecoxib
• APC Trial
• N=2,035 subjects
• Follow-up = 2.8-3.1 years
• CV deaths (%):
Rofecoxib
• APPROVe Trial
• N=2,586 subjects
• Follow-up = 3,327 pt-years
• CV Adverse events (%):
–Placebo (1%); RR=1.0
–200 mg BID (2.3%); RR=2.3
–400 mg BID (3.4%); RR=3.4
www.theoaklandpress.com;
www.washingtonpost.com;
4/7/05
12/18/04
N Engl J Med. 2005;352:1071-80
and 1092-102
–Placebo (2%); RR=1.0
–25 mg QD (3.6%); RR=1.9
Celecoxib and Colon Cancer
Prevention
• Psaty and Potter (NEJM 355:950, 2006)
– Reviewed APC and PreSAP trials and
concluded the following
– Celecoxib decreases adenoma formation
– Celecoxib increases the risk of cardiovascular
adverse events
– The potential increase in CV event/mortality
outweighs the projected decrease in colon
cancer incidence
Non-selective COX-2 inhibitors
• Retrospective data supporting potential
preventive effects
• Cardiovascular issues appear less, but
remain
• Aspirin
 Sandler et al. NEJM 348:883, 2003
 635 subjects with previous colo-rectal CA
randomized to ASA 325 mg/d or placebo
 1 or more adenomas in 27% of placebo vs 17% ASA
Calcium Polyp Prevention Study
Extended Follow-Up
• Self-reported surveys
(n=822)
• Mean = 7 yrs postintervention
• Histologic
confirmation for
adenomas
• 37% lower risk < 5 yrs
Grau, et al. – J Natl Cancer Inst 2007;99:129-36
Calcium + Vitamin D
Women’s Health Initiative
• Postmenopausal women
(n=36,282)
• 1000 mg elemental calcium +
400 IU vit. D3 vs. placebo
• Mean duration = 7.0 yrs
• Incident CRC (sec. endpoint)
• HR=1.1; 95% CI=0.9-1.3
0.010
0.006
0.002
0.000
0
1
2
3
4
5
6
7
8
= calcium + vitamin D
= placebo
Wactawski-Wende, et al. – N Engl J Med 2006;354:684-96
Nutraceutical Trials
Agent(s)
N
Fiber, Fat
201
Fiber, Fat, BC*
424
Fiber
1,429
Fiber, Fat, F&V†
2,079
Vitamins C, E
200
Vitamins C, E
864
Vitamin E
29,133
Selenium
598
Antioxidants + Calcium
93
Calcium
930
*Beta
carotene; †Fruits & vegetables
Endpoint Risk Estimate
Rec. adenoma 1.2 (0.6-2.2)
Rec. adenoma 1.2 (0.8-2.0)
Rec. adenoma 0.9 (0.7-1.1)
Rec. adenoma 1.0 (0.9-1.1)
Rec. adenoma 0.9 (0.5-1.5)
Rec. adenoma 1.1 (0.9-1.3)
Inc. cancer 0.8 (0.6-1.1)
Prev. adenoma 0.7 (0.4-1.1)
Rec. adenoma 0.3 (0.1-0.8)
Rec. adenoma 0.8 (0.7-1.0)
Meta-analysis of Antioxidants for GI Cancer Prevention
Bjelakovic et al. Lancet 364:1219, 2004
Meta-analysis of Antioxidants for GI Cancer Prevention
Overall Mortality
Bjelakovic et al. Lancet 364:1219, 2004
Statins and Colon Cancer
• Lipid lowering agents have been associated with
decreased incidence of various cancers
• Dale et al (JAMA 295:74, 2006) performed metaanalysis of randomized through 2005 and
observed no effect on cancer incidence or death
rate
• Poynter et al. (NEJM 352:2184, 2005) case control
study in Israel of approx 2000 colon cancer
patients vs 2000 controls; statin use of >5 yrs was
associated with a 50% risk reduction
Difluoromethylornithine (DFMO)
• DFMO is a specific polyamine inhibitor
approved for treatment of African Sleeping
sickness
• Phase 2 and 3 studies in other tissue sites
have observed safety and tolerability; longer
duration studies are pending including in
preventing colonic polyps
Chemoprevention of Colon Cancer
• Promising results with COX-2 inhibitors have
been severely compromised by other organ
toxicity
• Dietary measures or nutrient-based supplements
have mainly been negative, potential exceptions
include calcium ± vitamin D and selenium
• We continue to explore other options for the
chemoprevention of colon cancer
Chemoprevention of Colon Cancer
• Future directions
– Earlier markers of risk
• Protein signatures
• Aberrant crypt formation within colon
• Genomic signatures
– Less invasive measures of ongoing
chemopreventive effectiveness
• Finding the equivalent of checking your cholesterol
level for risk of heart disease
Chemoprevention of Colon Cancer
• Future directions cont.
– Combinations; low dose non-selective COX-2
inhibitors + other agents
• DFMO + sulindac
• Green tea + non-selective COX-2
– Test interventions as more health maintenance
rather than just trying to prevent a specific
cancer
• Studies like the Women’s Health Initiative
Colon Cancer Prevention
• Currently there are more established/costeffective measures to reduce the burden of
colo-rectal cancer;
• Chemoprevention of colon cancer currently
is not an established approach.
• For many reasons pursuing non-invasive
interventions for colon cancer risk reduction
is important.
Examples by Target Organ
Kelloff, et al. - Cancer Epidemiol Biomarkers & Prev 2000;9:127-37
Clinical Trials
Phase II
Trial(s)
25-75
50-300
1-12
6-36
pK, dose, SEB mod.
safety
Phase III
Trials
300+
36-60
cancer inc.
Cost
Subjects (N)
Duration (months)
Primary Endpoints
Phase I
Trial
Risk
Candidate
Agent
Chemoprevention Targets
General
• Proliferation
• Apoptosis
• Circulating growth
factors
• Immunosurveillance
• Metastasis
Specific
• Tumor necrosis factor
• Nuclear factor-kappa
B
• Activator protein-1
• STAT proteins
• Cyclooxygenase-2
• Lipoxygenases
Colorectal Cancer
Potential Cohorts
• Prior neoplasia
• Inflamm. bowel disease
Case Distribution
75%
- Crohn’s disease
- ulcerative colitis
• FAP
• HNPCC
• Family hx. NOS
4%
Sporadic
Familial NOS
HNPCC
15%
FAP
Other Syndromes
IBD
Chemoprevention Agents/Issues
with Micronutrients
 CARET, ATBC, and NPC Results
 Concerning negative results
 Micronutrients assumed not to be harmful
 Replacement doses vs supraphysiologic (prooxidant effects?)
 Regular dietary consumption vs
supplementation
 Smokers and gender differences in metabolism