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
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 (19702005) on the effectiveness of aspirin for the
chemoprevention of colic adenomas, CRC, and CRC
mortality, as well as potential harms.
4
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 0.610.85), 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
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
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 CRC changes 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
Coxibs Cardiovascular Toxicity
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
N Engl J Med. 2005;352:1071-80
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
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