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Colon Cancer Chemoprevention

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

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Colon Cancer Chemoprevention

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  1. 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

  2. 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

  3. Estimated new Cancer Cases for 2007 Jemal et al. CA Cancer J Clin 2007

  4. Estimated Cancer Deaths for 2007 Jemal et al. CA Cancer J Clin 2007

  5. Annual Age-adjusted Cancer Incidence Rates Jemal et al. CA Cancer J Clin 2007

  6. Annual Age-adjusted Death Rate Males Jemal et al. CA Cancer J Clin 2007

  7. Annual Age-adjusted Death Rate Females Jemal et al. CA Cancer J Clin 2007

  8. Incidence of Selected Cancers by Race/Ethnicity Jemal et al. CA Cancer J Clin 2007

  9. Death Rates for Cancers by Race/Ethnicity Jemal et al. CA Cancer J Clin 2007

  10. Colo-rectal Cancer Incidence JNCI Stat Bite, 2006

  11. 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.

  12. Mortality Rates Selected IHS sites Slattery, J Cancer Educ 2005

  13. 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

  14. 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

  15. 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

  16. Candidate Agents • COX-2 inhibitors, selective or non-selective • Diet and Nutraceuticals • Antioxidants/Vitamins • Statins • Difluoromethylornithine (DFMO) • Others

  17. 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

  18. 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 Selective COX-2 Inhibitors Steinbach, et al. - N Engl J Med 2000;342:1946-52; Images from E. Hawk, NCI

  19. 41 Polyps at Baseline 21 Polyps at Follow-Up Subject #5120 Images courtesy of Dr. E. Hawk, NCI

  20. - 11.9 -28.0%* 400 mg BID(N=30) 100 mg BID(N=32) Change in Polyp Number 80 60 40 20 0 % Change from Baseline - 4.5 -20 -40 -60 -80 Placebo(N=15) * p< 0.05; Steinbach, et al. - N Engl J Med 2000;342:1946-52

  21. 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 Advanced Adenomas Recurrent Adenomas Celecoxib Celecoxib 200 mg bid 200 mg bid Placebo bid Placebo bid Celecoxib Celecoxib 400 mg bid 400 mg bid Celecoxib Celecoxib 200 mg bid 200 mg bid Placebo bid Placebo bid Celecoxib Celecoxib 400 mg bid 400 mg bid Sporadic AdenomasPhase III Trials *p<0.0001 vs. placebo; Bertagnolli – NEJM 2006;355:873-84

  22. 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); adv. Phase III Trials N Engl J Med 2006;355:885-95 and Gastroenterol 2006; epub

  23. Rofecoxib APPROVe Trial N=2,586 subjects Follow-up = 3,327 pt-years CV Adverse events (%): Placebo (2%); RR=1.0 25 mg QD (3.6%); RR=1.9 Celecoxib APC Trial N=2,035 subjects Follow-up = 2.8-3.1 years CV deaths (%): Placebo (1%); RR=1.0 200 mg BID (2.3%) ; RR=2.3 400 mg BID (3.4%) ; RR=3.4 www.washingtonpost.com; 4/7/05 www.theoaklandpress.com; 12/18/04 Cardiovascular Toxicity N Engl J Med. 2005;352:1071-80 and 1092-102

  24. 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

  25. 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

  26. Extended Follow-Up Self-reported surveys (n=822) Mean = 7 yrs post-intervention Histologic confirmation for adenomas 37% lower risk < 5 yrs Calcium Polyp Prevention Study Grau, et al. – J Natl Cancer Inst 2007;99:129-36

  27. 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 = calcium + vitamin D = placebo Calcium + Vitamin D Wactawski-Wende, et al. – N Engl J Med 2006;354:684-96

  28. Nutraceutical Trials Agent(s)NEndpointRisk Estimate Fiber, Fat 201 Rec. adenoma 1.2 (0.6-2.2) Fiber, Fat, BC* 424 Rec. adenoma 1.2 (0.8-2.0) Fiber 1,429 Rec. adenoma 0.9 (0.7-1.1) Fiber, Fat, F&V† 2,079 Rec. adenoma 1.0 (0.9-1.1) Vitamins C, E 200 Rec. adenoma 0.9 (0.5-1.5) Vitamins C, E 864 Rec. adenoma 1.1 (0.9-1.3) Vitamin E 29,133 Inc. cancer 0.8 (0.6-1.1) Selenium 598 Prev. adenoma 0.7 (0.4-1.1) Antioxidants + Calcium 93 Rec. adenoma 0.3 (0.1-0.8) Calcium 930 Rec. adenoma 0.8 (0.7-1.0) *Beta carotene; †Fruits & vegetables

  29. Meta-analysis of Antioxidants for GI Cancer Prevention Bjelakovic et al. Lancet 364:1219, 2004

  30. Meta-analysis of Antioxidants for GI Cancer Prevention Overall Mortality Bjelakovic et al. Lancet 364:1219, 2004

  31. Statins and Colon Cancer • Lipid lowering agents have been associated with decreased incidence of various cancers • Dale et al (JAMA 295:74, 2006) performed meta-analysis 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

  32. 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

  33. 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

  34. 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

  35. 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

  36. Colon Cancer Prevention • Currently there are more established/cost-effective 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.

  37. Examples by Target Organ Kelloff, et al. - Cancer Epidemiol Biomarkers & Prev 2000;9:127-37

  38. Clinical Trials Candidate Agent Phase I Trial Phase II Trial(s) Phase III Trials Subjects (N) Duration (months) Primary Endpoints 25-75 1-12 pK, safety 50-300 6-36 dose, SEB mod. 300+ 36-60 cancer inc. Risk Cost

  39. General Proliferation Apoptosis Circulating growth factors Immunosurveillance Metastasis Specific Tumor necrosis factor Nuclear factor-kappa B Activator protein-1 STAT proteins Cyclooxygenase-2 Lipoxygenases Chemoprevention Targets

  40. Potential Cohorts Prior neoplasia Inflamm. bowel disease Crohn’s disease ulcerative colitis FAP HNPCC Family hx. NOS Case Distribution Colorectal Cancer

  41. Chemoprevention Agents/Issues with Micronutrients • CARET, ATBC, and NPC Results • Concerning negative results • Micronutrients assumed not to be harmful • Replacement doses vs supraphysiologic (pro-oxidant effects?) • Regular dietary consumption vs supplementation • Smokers and gender differences in metabolism

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