Chemoprevention of Colorectal Cancer: Where We Stand

Transcription

1 Chemoprevention of Colorectal Cancer: Where We Stand Andrew T. Chan, MD, MPH Division of Gastroenterology Massachusetts General Hospital 2 nd World Congress on Controversies in Gastroenterology Xi an, China September 13, 2014

2 Candidates Aspirin Celecoxib Menopausal hormone therapy Folate Calcium / Vitamin D Fiber Antioxidants

3 Colonoscopy: Effective but with limits No screening Colonoscopy screening All CRC ( ) Distal colorectal ( ) Proximal colon ( ) Nishihara et al, NEJM 2013

4 Aspirin and adenoma trials Trial N Duration Dose Relative Risk Baron, 1121 prior 3 years 81 mg 0.83 ( ) NEJM 2003 adenoma 325 mg 0.96 ( ) Sandler, NEJM 2003 Benamouzig, Gastro 2003 Logan, Gastro 2008 Ishikawa, Gut prior CRC 272 prior adenoma 945 prior adenoma 311 prior adenoma 3 years 325 mg 0.65 ( ) 1 year 160 mg 0.85 ( ) 300 mg 0.61 ( ) 3 years 300mg 0.79 ( ) 2 years 100 mg 0.60 ( )

5 Multivariate relative risk Duration of aspirin use and risk of CRC P for trend = < to 5 6 to to 20 > 20 Years of regular aspirin use Chan et al, JAMA 2005

6 Multivariate relative risk Aspirin and risk of GI bleeding P trend = < to to 5 6 to 14 > 14 Standard tablets of aspirin per week 1.83 Huang et al. Am J. Med 2011.

7 U.S. Preventative Services Task Force 2007 Recommends against routine use of aspirin or NSAIDs to prevent CRC in average risk individuals Harms outweigh the benefits for the prevention of CRC

8 Aspirin reduces CRC in Lynch after long-term follow-up Intention-to-treat HR=0.63; p=.12 Poisson IRR = 0.56; p=.05 Burn et al, Lancet 2011

9 C um ulativ e In c id enc e.016 Aspirin reduces risk of CRC: Colorectal Cancer 18 year follow-up of WHS Trial Aspirin Placebo p = No. at Risk Follow-up Years Aspirin Placebo Cook et al, Ann Int Med 2013

10 Aspirin reduces CRC mortality in cardiovascular prevention RCTs mg daily BDAT(500mg) UK-TIA (120 mg) mg daily UK-TIA (300 mg) TPT (75 mg) SALT (75 mg) Subtotal Total Rothwell et al, Lancet ( ) Odds Ratio (95% CI) 2 P=0.002(sig) P=0.84(het)

11 Aspirin reduces risk of overall cancer death in 8 CV RCTs Rothwell et al, Lancet 2011

12 Aspirin reduces risk of death from specific cancers Esophagus Stomach Pancreas Colorectal Lung Prostate Kidney/bladder Hematological Rothwell et al, Lancet 2011

13 Aspirin: Chemoprevention for multiple diseases? Established benefit for secondary prevention of vascular disease Strong evidence for benefit across multiple cancers Will the effects of aspirin on multiple cancers as well as CV disease tip the balance toward broader recommendations for prevention?

14 Coxibs and adenoma trials Trial N Agent Dose Outcome Bertagnolli, NEJM, Celecoxib 200 mg bid 400 mg bid 0.67 ( ) 0.55 ( ) Arber, NEJM, Celecoxib 400 mg qd 0.64 ( ) Baron, Gastro, Rofecoxib 25 mg 0.76 ( )

15 Event rate, % Celecoxib and risk of CV events Placebo OR, 3.4 (95% CI, ) OR, 2.6 (95% CI, ) 7 Solomon et al, NEJM Celecoxib 200 mg bid 23 Celecoxib 400 mg bid

16 Other effective agents Agent Efficacy Caveat Estrogen + Progestin Sulindac + DFMO Cancer, RR 0.56 ( ) Adenoma, RR 0.38 ( ) CV events? advanced CRC? Ototoxicity? CV events Bolland, BMJ 2011; Chlebowski, NEJM 2004 Meyskens, Can Prev Res 2008; Zell, Can Prev Res 2009

17 Ineffective agents Folate (may be effective in folate-deficient) Antioxidants Fiber supplements Cole, JAMA 2007; Logan, Gastro 2008; Giovannucci, Am J Clin Nutr 2009 Greenberg, NEJM 1994 Schatzkin, NEJM 2000; Alberts, NEJM 2000

18 Calcium Controversial 930 subjects - Calcium (1200 mg)/d reduced risk of recurrent adenoma (RR 0.81; CI, ) Calcium + Vitamin D 2259 subjects - Calcium (1200 mg) + Vitamin D3 (1000 IU)/d No risk reduction Baron, NEJM 1999 Baron, AACR 2014

19 Statins Metformin Fish oil Curcumin More data needed.

20 Summary Aspirin: Who should we treat? Lynch syndrome Colon cancer patients Patients with prior history of advanced adenoma After detailed discussion of risks/benefits, including consideration for dose I generally recommend standard dose (325 mg) but 81 mg may be sufficient Patients who are unable to undergo colonoscopic screening / surveillance Neugut, JAMA Int Med 2014

21 Summary Other agents Other effective agents have drawbacks (celecoxib, estrogen/progestin, sulindac/dfmo) Calcium likely safe, but data conflicting Vitamin D (1000 IU) ineffective Folate appears ineffective in a folate-replete population Further studies pending - high dose vitamin D, statin, metformin, fish oil