Transcript Chemoprevention of Cancer - Native American Programs

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