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Chemoprevention after polipectomy

Chemoprevention after polipectomy. Giuseppe Aprile Gianpiero Fasola Dipartimento di Oncologia Azienda Ospedaliero-Universitaria di Udine. Why is chemoprevention so complicated? Different studies with different endpoints, in different populations.

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Chemoprevention after polipectomy

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  1. Chemoprevention after polipectomy GiuseppeAprile Gianpiero Fasola Dipartimento di Oncologia Azienda Ospedaliero-Universitaria di Udine

  2. Why is chemoprevention so complicated? Different studies with different endpoints, in different populations Drug companies contributed to the land of confusion

  3. Candidate Agents • Aspirine • Other NSAIDs and COX-2 inhibitors • Difluoromethylornithine (DFMO) • Diet and Nutraceuticals • Antioxidants/Vitamins • Statins

  4. Systematic review of the available evidence (1970-2005) on the effectiveness of aspirin for the chemoprevention of colic adenomas, CRC, and CRC mortality, as well as potential harms.

  5. Bottom-line • Aspirina riduce il RR di adenoma colorettale in RCTs (RR 0.83, CI 0.7-0.95), studi caso-controllo (RR 0.75 CI 0.61-0.85), e in studi di coorte (RR 0.72, CI 0.61-0.85) • Se average-risk RR reduction nell’incidenza di adenoma 15-20%, possibliy higher se rischio maggiore • Contrastato il ruolo nella riduzione dell’incidenza di CRC (studi di coorte positivi, RCT negativi) • Dati insufficienti per mortalità • Benefici della chemioprevenzione più consistenti con uso di aspirina ad alte dosi per almeno 10 yrs • Possible harms (GI bleeding) require careful consideration

  6. Metanalisi di RCT sul ruolo dell’aspirina nella chemioprevenzione dell’adenoma colorettale Cole BF, et al. Aspirin for the chemoprevention of colorectal adenomas: meta-analysis of the randomized trials. JNCI 2009

  7. Is Adenoma Recurrence a Useful Surrogate for CRC Risk? Most small adenomatous polyps do not progress to malignancy Probability that a small adenoma contains high grade dysplasia/malignant changes is small (2%) Average transition time from small adenoma to invasive cancer > 10 years National Polyp Study. N Engl J Med,1993

  8. Number Needed to Treat (NNT) • Chemoprevention 10,000/15 = 700 treated for one cancer prevented 700 healthy people at risk for each person who benefits • Treatment of Disease (best case) 1 treated for one therapeutic effect 1 person at risk for each person who benefits

  9. Safety: Study Population Geriatric patient (>70 yrs, >85 yrs if surgeon) susceptibilities Severe drug toxicity Drug-drug interactions Potential for drug toxicity related to chronic administration Reduction of adenoma growth but dysplasia and CRCchanges may continue

  10. Selective COX-2 Inhibitors Celecoxib: 2001 FDA approved for adenomatous polyp prevention for individuals with FAP These data and retrospective data have led to extensive study of COX-2 inhibitors for sporadic adenomas as well

  11. 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 Coxibs Cardiovascular Toxicity N Engl J Med. 2005;352:1071-80 N Engl J Med. 2005;352:1092-102

  12. Celecoxib, CRC prevention, safety issues Psaty and Potter, N Engl J Med 2006 Reviewed APC and PreSAP trials and concluded: • 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

  13. Rofecoxib, CRC prevention, safety issues Kerr D et al. N Engl J Med 2007 Rofecoxib and cardiovascular adverse events in adjuvant treatment of CRC Reviewed VICTORe trial CV events, after a median treatment duration of 7.5 months: • Rofecoxib decreases adenoma formation • Rofecoxib significantly increases the risk of cardiovascular adverse events • RR for cardiovascular events 2.7 (CI 1.1-6.8)

  14. Do you see any improvement? 2000 2009

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