This was a randomised, double blind, placebo controlled study of the efficacy and safety of celecoxib in reducing percentage area of disease in the duodenum and improving the extent of duodenal polyposis. Eighty three patients with FAP, recruited from polyposis registries at St Mark's Hospital and at MD Anderson Cancer Center during their routine clinical follow up, were enrolled in the study (47 males, mean age 34 years). Seventy six of the 83 patients were tested for APC mutations and a mutation was identified in 70. Seventy seven patients with a retained colonic or rectal remnant containing a minimum of five adenomas were randomised 2:2:1 to receive 100 mg celecoxib twice daily (32 patients), 400 mg celecoxib twice daily (30 patients), and an identical looking placebo (15 patients). An additional six patients who had duodenal disease only were randomised 1:1:1 (table 1). All 83 patients were assessed for duodenal polyposis. Exclusion criteria included: patients who had undergone a colectomy within 12 months of entry to the study or who were anticipated to have a colectomy within eight months of randomisation; frequent use of NSAIDs or aspirin within six months or infrequent use within three months of randomisation; or abnormal serum laboratory values. Patients were blocked by site, the randomised code generated by GD Searle and Co. The study was monitored by the National Cancer Institute. Five patients did not complete the study, three due to adverse events and two because of non-compliance.
Patient demographics in the placebo and celecoxib 100 mg and 400 mg twice daily groups
After informed consent, patients underwent upper gastrointestinal endoscopy using diagnostic side viewing endoscopes (BPS, PML). The procedure was videotaped and photograph images taken of the ampulla, areas of dense polyposis, and areas of mild or no disease for later assessment. Biopsies of abnormal looking areas were taken for histology and further molecular biological studies (details not presented here). Examination was repeated after six months.
Following baseline endoscopy, patients were randomised and received the study drug. Safety and tolerability information was obtained at patient visits and structured interviews at weeks 2 and 4, followed by monthly contact until at least one month after completing treatment.
The study was approved by the MD Anderson Cancer Center Institutional Review Board and the ethics committee at St Mark's Hospital.
Results were analysed using two clinical methods. A qualitative assessment of the endoscopic appearance of duodenal polyposis was made during video review sessions. Five physicians (RKSP, MHW, MR-B, PML, GS), who were blinded to the treatment and control groups and also blinded as to which of the two paired tapes were before or after treatment, each scored all tapes. These were scored as no change, clinical improvement, or deterioration in adenoma number or density (scored as 0, 1, or −1).
In addition, a quantitative percentage change in adenoma density was calculated from measures of the per cent area covered by discrete and plaque-like adenomas in still photographs of two circumscribed areas of high and low density disease. The areas thought to be representative of the highest and lowest adenoma burden seen at the time of examination were chosen for the photographs at baseline and again at six months. These may not have been the same areas each time but gave a quantitative impression of overall activity in the duodenum. This method was used instead of photographing a specific point at baseline and at six months to avoid missing new areas of adenoma progression during the study where the chosen area may have shown regression. A grid placed over the photographs was used to estimate the percentage area covered by adenomas (plaque or discrete) and the mean of the low and high density scores was calculated.
Wilcoxon matched pairs signed rank sum tests were used to compare the mean per cent changes from baseline in duodenal areas covered with plaque-like adenomas, and the means of the videotape assessment scores between treatment groups. All tests were two sided at the 5% level of significance. Two patients who had duodenal polyposis at six months but not at baseline were given a baseline value of 1%. The qualitative assessment was assigned a score of (0) no change, (+1) clinical improvement, or (−1) deterioration in adenoma number or density.
Analysis of the physician assessment of the duodenal videotapes included all patients (n=78) for whom the requisite videotapes were available. For technical reasons (failure of videotaping equipment, etc) we were unable to review five tapes.
All randomised patients who had duodenal polyposis at baseline or at month 6 (n=50) were included in the quantitative analysis of the per cent change in duodenal areas covered with plaque-like adenomas. Because minimal disease is of minor clinical significance, a subanalysis of those with clinically measurable disease was also performed. The subgroup was defined as those in whom 5% or more of the high density photographed area was covered with adenomas.