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

Chemoprevention after polipectomy

GiuseppeAprile

Gianpiero Fasola

Dipartimento di Oncologia

Azienda Ospedaliero-Universitaria di Udine


Chemoprevention after polipectomy

Why is chemoprevention so complicated?

Different studies with different endpoints, in different populations

Drug companies contributed to the land of confusion


Candidate agents

Candidate Agents

  • Aspirine

  • Other NSAIDs and COX-2 inhibitors

  • Difluoromethylornithine (DFMO)

  • Diet and Nutraceuticals

  • Antioxidants/Vitamins

  • Statins


Chemoprevention after polipectomy

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

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


Chemoprevention after polipectomy

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

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

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

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

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


Coxibs cardiovascular toxicity

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

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

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)


Chemoprevention after polipectomy

Do you see any improvement?

2000

2009


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