In patients who develop adenocarcinomas, there is typically a progression from normal epithelium, through some inflammatory, metaplastic, or other intermediate stage, to dysplasia and invasive cancer. The progression is by no means invariable and indeed may be reversible. Colorectal cancer exemplifies this progression and serves as an excellent model for investigating opportunities in cancer prevention by means of various secondary (eg, polypectomy to remove the precursor adenoma) and primary (chemoprevention) strategies.
We and many others have begun to explore opportunities in colon cancer chemoprevention through clinical trials involving groups at increased risk of colorectal cancer: patients with familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, and sporadic adenoma. This article briefly reviews data from our large trial of a selective COX-2 inhibitor, describes the designs for our current hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis trials (as well as ongoing sporadic adenoma trials), and includes comments on trials with other agents.
Patients with familial adenomatous polyposis have a germline mutation in the adenomatous polyposis coli (APC) gene. The consequence of this is the development of hundreds of adenomas, typically during adolescence. If untreated, as by prophylactic colectomy or proctocolectomy, the risk of colorectal cancer is nearly 100%. Following colectomy, subjects remain at risk of duodenal carcinoma and, if proctectomy is not performed, of rectal cancer; these areas have hence been targeted in surveillance and chemoprevention interventions.
Historically, cancer prophylaxis has consisted of colectomy followed by proctosigmoidoscopic surveillance and ablation of recurrent rectal polyps, or more recently and aggressively, prophylactic proctocolectomy with restorative ileal pouch reservoir/anal anastomosis. Management of risk of duodenal neoplasia has been particularly vexing because of the variable natural history of duodenal adenomas; the lack of effective, safe endoscopic measures to ablate the flat, spreading lesions; and the morbidity associated with aggressive surgical interventiontypically pancreaticoduodenectomy.
Though prophylactic surgical interventions are well accepted in familial adenomatous polyposis, the possibility of medical approaches has been explored. The nonsteroidal anti-inflammatory drug (NSAID) sulindac(Drug information on sulindac) has been reported to cause complete or near-complete regression of rectal adenomas, initially in uncontrolled trials[2-4] and later in placebo-controlled investigations. More modest regression of rectal adenomas has been reported in two larger placebo-controlled studies.[6,7] No cases of complete regression were observed, and adenomas recurred within several months of cessation of the sulindac.[5,6] No long-term efficacy studies of sulindac have been carried out, and there are case reports of cancers occurring while taking sulindac.
Hereditary nonpolyposis colorectal cancer has until recently been a clinical diagnosis involving the familial pattern of early-onset and/or multiple primary colorectal cancer, with or without the presence of certain extracolonic tumors. In many families colon tumors cluster in the right colon. Adenomas may be completely absent and rarely number more than a few. The mode of inheritance for hereditary nonpolyposis colorectal cancer is autosomal dominant, with penetrance for colorectal cancer estimated at about 80% by age 70. The mean age at cancer onset is approximately 45 years but ranges from 20 to 80+ years, thus overlapping with the age distribution of sporadics.
Stomach and small bowel adenocarcinomas occur in excess, but are sufficiently infrequent that surveillance is not usually recommended. In addition to colorectal and other gastrointestinal tumors, hereditary nonpolyposis colorectal cancer includes a number of extraintestinal tumors. Lacking any pathognomonic features, the significance of any given tumor in a particular patient is problematic. Tumors most commonly involve the endometrium, followed by the ovary and the uroepithelium (ureter and renal pelvis). Peculiar skin tumors (sebaceous adenoma, carcinoma, and keratoacanthoma) occur in a subset of families with the so-called Muir-Torre syndrome.
As in familial adenomatous polyposis, the management of hereditary nonpolyposis colorectal cancer involves recognition of risk, followed by appropriate surveillance and surgical intervention. All must be enhanced, compared to the average-risk patient. In a sufficiently striking family, colorectal cancer risk to offspring of affected parents approaches 50%. Molecular genetic testing will detect mutations in one of the "hereditary nonpolyposis colorectal cancer genes" in up to 85% of families.
Assuming such a mutation is identified, offspring of affected parents can be segregated into two groups: those at population risk (noncarriers) and those whose risk approaches 100% (carriers). In carriers, colonoscopy is recommended, beginning at age 20 to 30 and repeated at intervals of 1 to 5 years (the broad range reflects a lack of hard data and a lack of consensus among experts). Noncarriers will require no further enhanced evaluation, assuming accuracy of the genetic testing.
When adenocarcinomas are detected, subtotal colectomy with ileorectal anastomosis is urged. Residual risk to the rectum exists postcolectomy, but its magnitude is uncertain and probably not great enough to warrant proctectomy. The approach to the patient with an adenoma is uncertain. Most would perform simple endoscopic polypectomy, but the possibility of prophylactic colectomy may be increasingly considered in known mutation carriers, particularly when difficult-to-remove right-sided sessile lesions are involved. Surveillance for extracolonic tumors has received little attention.
The chronology of molecular advances in hereditary nonpolyposis colorectal cancer is interesting. Unlike familial adenomatous polyposis, there was no good clue as to the possible location of a susceptibility locus, though several "candidate" loci, such as the APC, p53, and DCC (deleted in colorectal carcinoma) genes, were evaluated and excluded. Rather, establishing genetic linkage in hereditary nonpolyposis colorectal cancer required a search through the human genome, facilitated by the developing library of known, linked genetic polymorphisms.
In 1993 such linkage was established to a locus on chromosome 2 and quickly confirmed. Within a year, the gene had been cloned and found to show homology in nucleotide sequence to a member of a yeast DNA "mismatch repair" gene (MutS). Because linkage studies at this locus had failed to account for a majority of families that appeared to have hereditary nonpolyposis colorectal cancer, additional loci were evaluated and a second gene identified. When cloned, this gene was also found to show homology to a member of the yeast mismatch repair family of genes.
It was then concluded that perhaps other human genes from this mismatch repair family might also account for cases of hereditary nonpolyposis colorectal cancer. The library of human DNA sequences was searched to determine if there were other areas that showed significant homology to the other representatives of the mismatch repair genes of lower species. Several additional human mismatch repair genes were identified and found to account for a small proportion of hereditary nonpolyposis colorectal cancer families.
As in the case of familial adenomatous polyposis, each of these discoveries carried potential implications for management. Establishment of linkage enabled recognition of carriers of susceptibility through performance of linkage analysis utilizing polymorphic flanking markers. Cloning of the genes enabled direct testing of individual affected members of hereditary nonpolyposis colorectal cancer families, without having to resort to linkage analysis.