Chemoprevention after polipectomy

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Chemoprevention after polipectomy

• Giuseppe Aprile
• Gianpiero Fasola
• Dipartimento di Oncologia
• Azienda Ospedaliero-Universitaria di Udine

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

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

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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.
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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 nellincidenza di
  adenoma 15-20, possibliy higher se rischio
  maggiore
• Contrastato il ruolo nella riduzione
  dellincidenza 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

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Metanalisi di RCT sul ruolo dellaspirina nella
chemioprevenzione delladenoma colorettale
Trial and ref. N Pop Treatment Prevention of any adenoma Prevention of advanced adenoma
AFPPS Baron JA NEJM 2003 1120 Sporadic adenoma Placebo vs asp-81 vs asp-325 /-FA
CALGB 9270 Sandler R NEJM 2003 635 Previuos CRC Placebo vs asp-325 -
UK-CAP Logan R Gastroenterology 2008 940 Sporadic adenoma Placebo vs asp-300
APACC Benamouzig R, Gastroenterology 2003 270 Sporadic adenoma Placebo vs asp-160 vs asp-300 /- /-
Cole BF, et al. Aspirin for the chemoprevention
of colorectal adenomas meta-analysis of the
randomized trials. JNCI 2009
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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 gt 10 years
• National Polyp Study. N Engl J Med,1993

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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

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Safety Study Population

• Geriatric patient (gt70 yrs, gt85 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 CRC
  changes may continue

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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

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Coxibs Cardiovascular Toxicity

• Rofecoxib
• APPROVe Trial
• N2,586 subjects
• Follow-up 3,327 pt-years
• CV Adverse events ()
• Placebo (2) RR1.0
• 25 mg QD (3.6) RR1.9

• Celecoxib
• APC Trial
• N2,035 subjects
• Follow-up 2.8-3.1 years
• CV deaths ()
• Placebo (1) RR1.0
• 200 mg BID (2.3) RR2.3
• 400 mg BID (3.4) RR3.4

N Engl J Med. 20053521071-80
N Engl J Med. 20053521092-102
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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

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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)

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Do you see any improvement?
2000
2009
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