Most patients are eligible for chemoprevention because proctocolectomy with IPAA or a colectomy with ileorectal anastomosis can retain at-risk rectal mucosa, and the duodenal mucosa remains at risk in all these patients. It should be noted that although no drug, including those described here, is approved by the Food and Drug Administration for the indication of chemoprevention, several drugs have been studied in over a dozen randomized controlled trials and in many observational studies (Table 5).81–96 Of 4 trials examining the use of sulindac, 3 reported positive findings.81–84 The negative trial was a primary prevention trial in patients who were phenotypically unaffected but had APC mutations. These findings may not be applicable to the postoperative population of patients with a highly penetrant polyposis phenotype.84 One trial evaluating dual treatment with sulindac and erlotinib for duodenal polyp suppression was stopped early because of the superiority of the chemoprevention over placebo, although there was a high rate of grade 1 and 2 adverse events, including an acne-like rash in 87% of treated patients.85 Of 7 trials examining the role of selective cyclooxygenase-2 inhibition, 6 reported positive results.86–92 An international randomized controlled trial of celecoxib and difluoromethylornithine showed that the addition of difluoromethylornithine was required to achieve a benefit in reduction of adenoma count when compared with placebo.91 Another trial examined eicosapentaenoic acid with positive results.93 Three studies have examined vitamin C, vitamin E, calcium, or a combination, with mixed but overall negative results.94–96
Substantial evidence supports the use of chemoprevention in patients who have polyposis with duodenal adenomas or at-risk rectal mucosa. Sulindac has a higher rate of gastritis than celecoxib; in patients over age 65, or who have a history of a peptic ulcer, or who require concurrent use of aspirin, corticosteroids, or anticoagulants for other medical problems, sulindac should usually be given with a proton-pump inhibitor.97,98 The risk of adverse events or GI bleeding, as well as issues with compliance, cost, or patient preference, however, may preclude the use of chemoprevention in all or even many cases. It is important to note that chemoprevention should not replace routine endoscopic surveillance, that the role of chemoprevention for the suppression of polyps in the retained rectum is extrapolated from the duodenal adenoma studies, and that compliance with long-term treatment has not been well studied.
Between 20% and 50% of patients with oligopolyposis will not have a mutation found in the APC or MYH genes.13,99–101 Multiple case series have identified alterations that are not included in existing commercial testing that may play a role in polyposis, such as genomic rearrangements involving APC, APC mosaicism, and mutations in the APC promoter.102–104 Other patients may harbor rare or as yet unknown causes of polyposis, such as the recently described polymerase proofreading-associated polyposis.105
Management of patients with mutation-negative polyposis has been described in observational studies. Tieu et al100 described 27 patients with multiple colorectal adenomas with a phenotype similar to attenuated polyposis with an average of 51 polyps. Eighteen patients (67%) underwent colectomy after a mean of 3.1 years after diagnosis due to the concern for cancer or for an inability to provide endoscopic clearance. Extracolonic findings in these patients may mirror attenuated polyposis syndromes as EGD-identified polyps in 47% of patients. A second observational study of patients with APC mutation-negative polyposis, however, showed they were less likely to display extracolonic manifestations.106 In the absence of a genetic defect, it is reasonable to treat patients according to their phenotype by maintaining endoscopic clearance in patients when possible and proceeding with colectomy or proctocolectomy if required according to the polyp number.
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