Chemoprevention for Inherited Colorectal Cancer

Abstract

Before the responsible susceptibility loci were discovered in the late 1980s and early 1990s, management of Familial Adenomatous Polyposis (FAP) and Hereditary Nonpolyposis Colorectal Cancer (HNPCC) were based on endoscopic surveillance of individuals whose parents had already manifested adenomatosis or cancer. In best case scenarios, early progression of adenomas in FAP or early cancer in HNPCC, ``curative{''} surgery would be performed, though cancer risk remained in any remaining colorectal segment and in the UGI tract. With discovery of the APC gene for FAP and the mismatch repair (MMR) genes for HNPCC, a more targeted approach became possible, with attention being limited to proven carriers. This encouraged earlier surveillance and, along with improved endoscopic management, enabled some patients to be followed conservatively for a period of time before prophylactic surgery was performed. At about the same time, development of medical measures, as opposed to mechanical (surgical and endoscopic) interventions began to take shape. Early dietary and micronutrient interventions have largely been disappointing. Nonsteroidal anti-inflammatory agents (NSAIDs) are currently the mainstay of medical management, with sulindac the most widely used. Due to the well-known side effects of traditional NSAIDs, selective COX-2 inhibitors have been studied rather extensively. Celecoxib has shown benefit in regressing colorectal adenomas and appears to have some favorable duodenal activity as well. Cardiovascular risks of both selective and nonselective COX-2 inhibitors provide a note of caution, though the balance of risks and benefits in this high-risk population differs from that in sporadic adenoma patients in whom the issue of cardiovascular risk was first raised. Because complete, durable responses are rare, the current and projected clinical trials are focusing on new agents and combinations of agents. Often overlooked has been the evolution of principles to guide the conduct of clinical chemoprevention trials. In this chapter, we will summarize the experience with chemoprevention in FAP and HNPCC. Critical attention will be devoted to those issues of trial design that determine the propriety of existing treatment recommendations.