Any of these conditions is amenable to chemoprevention strategies but most are too rare and lack clear relevance to the general population. Two conditions stand out as targets because they are well-defined and can act as a model for common cancers;

FAP captured clinical attention in the early twentieth century when it became clear that young people would develop hundreds, sometimes thousands, of adenomatous polyps in the colorectum leading without intervention to inevitable) death from colorectal cancer by early middle age (Burn et al.1991). Prophylactic colectomy with ileorectal anastomosis offered hope to these families where the faulty gene is transmitted as a fully penetrant autosomal dominant trait meaning that a child born to an affected parent had a 50 % chance of inheriting the faulty gene and developing the syndrome.

Systematic registries supported early gene mapping efforts and once the gene had been localised to chromosome 5q by a report of a man with FAP and learning difficulties due to a 5q deletion (Herrera et al. 1986) it took only a few months to localise and then identify the APC gene (Bodmer et al. 1987). Molecular genetic studies combined with more sophisticated clinical evaluation based on the detection of extra colonic features, particularly characteristic pigmented lesions of the retina known as congenital hypertrophy of the retinal pigment epithelium (CHRPE) resulted in highly effective family identification and more extensive endoscopic surveillance and prophylactic surgery (Burn et al. 1991).

The status of the disease was raised significantly once it became apparent that the large APC gene which harboured the hereditary defects in FAP was also usually mutated in CRC and that mutations were evident in the earliest adenomas. Somatic mutations in the APC gene are considered an initiating event in around 85 % of CRCs making FAP patients a powerful model for CRC chemoprevention studies. In essence, the cancer in an FAP gene carrier is identical to the commonest cancers in the general population. The primary difference is that in “sporadic cancer” both alleles of the APC gene must be lost in the same viable cell for neoplasia to get going where as every cell in the FAP gene carrier has one defective copy of the APC gene so only a single mutation is needed and there are millions of opportunities for that second event to occur.

There has been a long-standing interest in non-steroidal anti inflammatories in FAP. Labayle et al. (1991) reported that sulindac causes regression of rectal polyps in a randomized, placebo-controlled, double-blind crossover study in 10 patients with rectal polyps that had been previously treated by colectomy and ileorectal anastomosis. Patients received sulindac, 300 mg/day, or placebo during two 4-month periods separated by a 1-month wash-out phase. One patient was not compliant and was excluded. With sulindac, the authors observed a complete (six patients) or almost complete (three patients) regression of the polyps. With placebo, the authors observed an increase (five patients), no change (two patients), and a relative decrease (two patients) in the number of polyps. The difference between sulindac and placebo was statistically significant (p < 0.01). In biopsy specimens of polyps and normal rectal mucosa of six patients, the authors conducted an immunohistochemical study of the cellular proliferation index using the Ki 67 monoclonal antibody (Ki 67 index), at the beginning and at the end of each treatment period. They were not able to show a sulindac-induced modification of the Ki 67 index. The authors conclude that sulindac is effective in inducing the regression of rectal polyps in FAP. Giardiello et al. (1993) conducted a randomized, double-blind, placebo-controlled study of 22 patients with FAP, including 18 who had not undergone colectomy. The patients received sulindac at a dose of 150 mg orally twice a day for nine months or identical-appearing placebo tablets. The number and size of the polyps were evaluated every 3 months for 1 year. A statistically significant decrease in the mean number of polyps and their mean diameter occurred in patients treated with sulindac. When treatment was stopped at 9 months, the number of polyps had decreased to 44 % of baseline values and the diameter of the polyps to 35 % of baseline values (p = 0.014 and p < 0.001, respectively, for the comparison with the changes in the group given placebo). No patient had complete resolution of polyps. Three months after treatment with sulindac was stopped, both the number and the size of the polyps increased in sulindac-treated patients but remained significantly lower than the values at baseline. No side effects from sulindac were noted.

Nugent et al. (1993) studied sulindac in 24 FAP patients who had previously undergone prophylactic colectomy and had advanced duodenal polyposis; they were entered into a randomized trial to assess the effect of sulindac on duodenal and rectal polyps. Polyp size and number were assessed by videotaped duodenoscopy (and rectoscopy in 14 patients) at entry and after 6 months of treatment; the tapes were compared by two assessors who were unaware of the randomization and the shuffled chronological order of the recordings. Mucosal cell proliferation was measured by in vitro incorporation of 5-bromo-2′-deoxyuridine. Sulindac therapy was associated with a reduction in epithelial cell proliferation in the duodenum (median labelling index (LI) 15.8 versus 14.4 %, p = 0.003) and a trend towards duodenal polyp regression (p = 0.12). In the rectum, cell proliferation showed a marked reduction (median LI 8.5 versus 7.4 %, p = 0.018), and significant (p = 0.01) polyp regression was seen. Rectal polyposis was less severe than that in the duodenum and responded more dramatically.

A small study involving 12 FAP patients supported sulindac use (Cruz-Correa et al. 2002). Five women and seven men with men of age 37 years who had undergone ileorectal anastomosis received a mean dose of 158 mg/day for a mean period of 63.4 ± 31.3 months (range 14–98) and were followed every 4 months. Half remained polyp-free and there was a significant regression of polyps in all participants (p = 0.006). Prevention of recurrence of higher grade adenomas (tubulovillous, villous adenomas) was also observed (p = 0.004). At 35 months of follow-up, one patient developed stage III cancer in the rectal stump. The most common side effect was rectal mucosal erosions in six patients. Long-term use of sulindac was deemed to be effective in reducing polyp number and preventing recurrence of higher grade adenomas in the retained rectal segment of most FAP patients focused on the anti-inflammatory sulindac which acts as a pro drug. Metabolism in the gut converts it into the active form. They found a significant impact on polyp formation but there were some concerns about benefits in the long term.

Enthusiasm for the use of sulindac was diminished by reports of cancers emerging in rectal segments despite apparent suppression of polyp formation (Lynch et al. 1995). This may explain the disappointing results from the long-term follow-up analysis by Giardiello et al. (2002); After 4 years of treatment with either 75 or 150 mg sulindac in an RCT, 41 FAP subjects had achieved 76 % compliance. 43 % of the sulindac versus 55 % of the placebo (p = 0.54) developed polyps. There was no significant difference in polyp size or mean number.

Cyclo oxygenase exists in two forms, COX1 and COX2; the former is constitutive and its inhibition underlies the gastrointestinal toxicity of aspirin and other non-steroidals. COX2 is upregulated in inflammation prompting a search for agents which were more COX2 selective. The selective COX2 inhibitors proved to be highly effective and well tolerated leading to widespread use in the management of arthritic conditions. Recognition of the upregulation of COX2 in early colorectal cancer prompted studies of the more popular agents as cancer chemopreventives.

Steinbach et al. (2000) investigated the effects of the selective COX2 inhibtor celecoxib in FAP. In a double-blind, placebo-controlled study, they randomly assigned 77 patients to treatment with celecoxib (100 or 400 mg twice daily) or placebo for 6 months. Patients underwent endoscopy at the beginning and at the end of the study. They determined the number and size of polyps from photographs and videotapes; the response to treatment was expressed as the mean percent change from baseline.

At baseline, the mean (±SD) number of polyps in focal areas where polyps were counted was 15.5 ± 13.4 in the 15 patients assigned to placebo, 11.5 ± 8.5 in the 32 patients assigned to 100 mg of celecoxib twice a day and 12.3 ± 8.2 in the 30 patients assigned to 400 mg of celecoxib twice a day. After 6 months, the patients receiving 400 mg of celecoxib twice a day had a 28.0 % reduction in the mean number of colorectal polyps (p = 0.003 for the comparison with placebo) and a 30.7 % reduction in the polyp burden (the sum of polyp diameters) (p = 0.001), as compared with reductions of 4.5 and 4.9 %, respectively, in the placebo group. The improvement in the extent of colorectal polyposis in the group receiving 400 mg twice a day was confirmed by a panel of endoscopists who reviewed the videotapes. The reductions in the group receiving 100 mg of celecoxib twice a day were 11.9 % (p = 0.33 for the comparison with placebo) and 14.6 % (p = 0.09), respectively. The incidence of adverse events was similar among the groups. It is noteworthy that the effects were more convincing with the larger 400 mg twice daily dose which exceeds the levels at which the drug is Cox2 selective.

Huang et al. (2011) similar beneficial effects in their study of 54 celecoxib treated FAP carriers with 13 controls. The Kaplan–Meier estimated probability of not having a polypectomy 12 and 60 months post- ileorectal anastomosis in the celecoxib-treated patients (n = 33) was 60.6 and 42.2 %, respectively. The estimated probability of not having a polypectomy 6–60 months post-ileal pouch-anal anastomosis the celecoxib-treated patients (n = 24) was 100 %. The median total daily dose of celecoxib was 698.9 mg with the majority treated for more than 24 months. There was one case of a rash attributed to the treatment.