Chemoprevention after polipectomy
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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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Chemoprevention after polipectomy

GiuseppeAprile

Gianpiero Fasola

Dipartimento di Oncologia

Azienda Ospedaliero-Universitaria di Udine


Why is chemoprevention so complicated?

Different studies with different endpoints, in different populations

Drug companies contributed to the land of confusion


Candidate Agents

  • Aspirine

  • Other NSAIDs and COX-2 inhibitors

  • Difluoromethylornithine (DFMO)

  • Diet and Nutraceuticals

  • Antioxidants/Vitamins

  • Statins


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.


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


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


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


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


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


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


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


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


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)


Do you see any improvement?

2000

2009


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