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Preventing colorectal adenomas

Randomised trials
Results
Comment

Bandolier 129 had a quick review of trials of aspirin, coxibs, and NSAIDs to prevent polyp recurrence in familial polyposis or prevention of adenomas. In familial polyposis there was some evidence that coxibs and NSAIDs may prevent polyp recurrence, but trials tended to be small and short. Three trials of low dose aspirin to prevent colorectal adenomas were longer (2.5 to 4 years) and larger (about 2,000 patients in total), and tended to show some reduction in adenoma formation, by about 10%.

We now have results from two [1,2] large and relatively long trials comparing celecoxib at various doses with placebo. What makes these interesting is not only the results on adenoma prevention, and possibly about colorectal cancer prevention, but also what they tell us about adverse events in trials of longer duration than those in arthritis, where duration is often little longer than three months.

Randomised trials


Protocols were similar for both trials. Patients enrolled were aged over 30 years and had undergone colonoscopy within three to six months and had an adenoma of at least 6 mm, or 2-10 adenomas of any size. Polyps were removed before the start of the trial, and all adenomas were confirmed by a central pathologist, with adjudication in case of disagreement between local and central pathologists. Excluded were patients with familial polyposis, hereditary bowel cancers, or various other bowel disease or surgery, together with sensible medical exclusions. Use of NSAIDs or full dose aspirin was not allowed, and use of analgesics limited.

Trials were both randomised and double blind. In one [1] celecoxib was 400 mg or 800 mg daily in divided doses, and in the other [2] 400 mg once daily. The primary outcome was detection of an adenoma during colonoscopy, with the secondary outcome of advanced adenoma (larger than 1 cm with various histological criteria). Trials were intended to last three years with colonoscopy at one and three years.

Results


Patients (over 3,500 randomised) were aged about 60 years on average (range 30 to 92 years), were predominantly (90%) white, and male (70%). An average of two adenomas had been reported, about 40% of which were larger than 1 cm. Low dose aspirin use was 30% in one trial [1] and 20% in the other [2]. There was a 10% discontinuation rate in both studies, mainly because of failure to undergo colonoscopy. Both trials were stopped early because of fears over cardiovascular adverse events with coxibs, so that they actually lasted about 2.5 years.

Efficacy and adverse event results are in Table 1, where all celecoxib dose regimens were combined for comparison with placebo. Celecoxib reduced the appearance of any adenoma, and advanced adenomas. The cumulative incidence of adenomas detected over three years in the two trials is shown in Figure 1. There were a small number of colorectal cancers (14) detected, with no difference between celecoxib and placebo. The results were not substantially different for aspirin use or non-use, and slightly better for patients who were 80% compliant or more for most of the trial.


Figure 1: Cumulative rate of ademonas over three years with placebo and celecoxib






Celecoxib was not associated with any difference with placebo for all-cause mortality or gastrointestinal haemorrhage (nor for anaemia in one trial [2]). There was no difference between celecoxib and placebo for serious adverse events. Celecoxib was associated with higher rates than placebo of renal or hypertensive disorders, investigator reported cardiovascular disorders, and independently adjudicated APTC endpoints (Table 1).


Table 1: Efficacy and adverse events pooled from two polyp trials with celecoxib and placebo



Event rate (%) with
Outcome
Placebo
Celecoxib
Relative risk
(95% CI)
NNTp/NNH
(95% CI)
Efficacy
NNTp
Any adenoma at colonoscopy: year 1
39
24
0.61 (0.55 to 0.68)
6.9 (5.6 to 8.9)
Any adenoma at colonoscopy: year 3
27
18
0.65 (0.55 to 0.77)
11 (7.6 to 19)
Advanced adenoma at colonoscopy: year 1
9.2
3.3
0.35 (o.26 to 0.47)
17 (13 to 25)
Advanced adenoma at colonoscopy: year 3
5.2
3.1
0.57 (0.39 to 0.83)
47 (27 to 220)
Colorectal cancers reported or on colonoscpy
0.3
0.4
1.44 (0.47 to 4.45)
not calculated
Adverse events
NNH
All-cause mortality
1.0
1.3
1.27 (0.66 to 2.45)
not calculated
Adjudicated APTC events
1.5
2.8
1.94 (1.16 to 3.25)
74 (44 to 250)
Investigator-reported cardiovascular disorders
4.6
7.4
1.61 (1.21 to 2.15)
36 (23 to 81)
Gastrointestinal ulceration or haemorrhage
11
12
1.05 (0.87 to 1.27)
not calculated
Renal or hypertensive disorders
17
22
1.24 (1.08 to 1.43)
22 (14 to 56)
NNTp = number needed to treat to prevent an event; NNH = number needed to harm



Comment


In many ways the results of these two trials comparing celecoxib with placebo for preventing colorectal adenomas are similar to those using low dose aspirin. Aspirin reduced adenomas with an NNTp of about 16, and also had a higher rate of heart attack and stroke compared with placebo. The heart attack and stroke rate with low dose aspirin (1.3%) was the same as the APTC rate with celecoxib in these two trials (1.3%).

These two reports are detailed, especially with regard to adverse event reporting. The increased rates of renal or hypertensive disorders are not unexpected with a coxib or NSAID in the present state of knowledge. The results confirm that celecoxib, with or without low dose aspirin, does not cause gastrointestinal bleeding.

There are good reasons why cyclooxygenase inhibition might prevent colorectal cancer. Cyclooxygenase-2 appears to be over-expressed in human cancers, and this seems to be related to poor survival. Inhibition might reduce cell proliferation and angiogenesis, and induce apoptosis. There may be cyclooxygenase independent effects. There is considerable observational evidence that regular aspirin or NSAID reduces cancer incidence, particularly colorectal.

Despite this biological plausibility, properly conducted clinical trials might not give the answers we want. These two, and others, have opened an industrial-sized can of worms, in part because they were so good in collecting and reporting adverse events. We are still in the experimental stage when it comes to knowing if or how to use these agents for colorectal cancer prevention.

References:

  1. M Bertagnolli et al. Celecoxib for the prevention of sporadic colorectal adenomas. New England Journal of Medicine 2006 355:873-884.
  2. N Arber et al. Celecoxib for prevention of colorectal adenomatous polyps. New England Journal of Medicine 2006 355: 885-895.

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