Benefits of Colonoscopic Surveillance and Prophylactic Colectomy in Patients with Hereditary Nonpolyposis Colorectal Cancer Mutations

Colorectal cancer is the second leading cause of cancer-related death in the United States [1]. Up to 15% of patients with colorectal cancer have a first-degree relative with the disease [2, 3]. In most cases, risk for colorectal cancer is likely to be a complex interaction of genetic and environmental factors. In a subset of patients, however, increased susceptibility to colorectal cancer is inherited through a single gene mutation. Genetic testing for predisposition to cancer is now possible for many hereditary syndromes, including hereditary breast and ovarian cancer, multiple endocrine neoplasia, von Hippel-Lindau disease, familial adenomatous polyposis, and hereditary nonpolyposis colorectal cancer. Hereditary nonpolyposis colorectal cancer, the most common hereditary colon cancer syndrome [4], is a dominantly inherited disease that is estimated to account for approximately 2% to 5% of colorectal cancers [5, 6]. The isolation of several DNA mismatch repair genes (hMSH2, hMLH1, hPM2, and hMSH6) associated with hereditary nonpolyposis colorectal cancer has made it possible to identify carriers of a mutated gene within a family [7-11]. On the basis of literature review and expert opinion, investigators from the National Human Genome Research Institute Cancer Genetics Studies Consortium recently recommended that carriers of a mutation for hereditary nonpolyposis colorectal cancer undergo regular colonoscopic surveillance every 1 to 3 years [12]. However, because of the high risk for cancer and metachronous tumors and the limitations of surveillance, the panel recommended that subtotal colectomy with ileorectal anastomosis be considered in patients with colon cancer or adenomas and total proctocolectomy be considered in those with rectal cancer [12]. A definitive answer to the optimal management approach for carriers of a mutation will require clinical studies of large numbers of patients followed prospectively over a long time. However, with the increasing use of genetic predisposition testing, patients and health care providers must decide on cancer risk-reduction strategies now. This decision involves weighing several factors, including the high risk for cancer; surgical and procedure-associated risks; and the health-related quality of life associated with prophylactic colectomy, endoscopic surveillance, and having cancer. We used a decision analysis to assess the outcomes of various colorectal cancer preventive strategies, including colonoscopic surveillance, prophylactic colectomy, and delayed colectomy for patients carrying a genetic mutation associated with hereditary nonpolyposis colorectal cancer. Methods Model Structure We constructed a Markov model by using the decision analysis program DATA (TreeAge Software, Inc., Williamstown, Massachusetts) to compare different approaches to colorectal cancer prevention in patients with a mutation for hereditary nonpolyposis colorectal cancer. The model follows a hypothetical cohort of patients over time and tracks the annual incidence of polyps and colorectal cancer (by stage), progression of colorectal cancer, and mortality (Figure 1). Short-term mortality associated with surgery and endoscopic surveillance was also incorporated. Figure 1. General model framework. Standard therapy for average-risk patients with colorectal cancer is segmental resection of the involved colon and appropriate stage-specific therapy for advanced disease. More aggressive prophylactic colonic resection as a cancer prevention method is the only management option for patients with familial adenomatous polyposis, another group at high risk for colorectal cancer. We evaluated two types of colectomy for carriers of a mutation for hereditary nonpolyposis colorectal cancer: proctocolectomy with ileoanal anastomosis, which was assumed to eliminate all risk for colorectal cancer and the need for postoperative surveillance, and subtotal colectomy with ileorectal anastomosis, which required continued surveillance of the remaining rectal segment. It has been recommended that at-risk patients from families with hereditary nonpolyposis colorectal cancer begin surveillance at 25 years of age or when they are 5 years younger than the youngest age at which cancer was diagnosed in a family member [5]. Because our analysis deals with mutation carriers, we adopted the more aggressive surveillance approach and assumed that surveillance began at 25 years of age. Surveillance was defined as colonoscopy every 3 years if no surgical intervention had been performed [13] and flexible sigmoidoscopy of the remaining rectal segment every 3 years after subtotal colectomy. Surveillance was assumed to stop at 85 years of age. All colorectal cancer was assumed to arise from colorectal adenomas [14-18], and adenomas detected by surveillance were assumed to be removed at the time of colonoscopy. The incidence of adenomas was assumed to be the same as that of cancer except that adenomas could be detected by colonoscopy 5 years before cancer was detected [19]. We examined the following 12 strategies for a cohort of 25-year-old patients who are cancer-free and have a known mutation for hereditary nonpolyposis colorectal cancer: immediate prophylactic proctocolectomy, immediate prophylactic subtotal colectomy, surveillance until 40 years of age followed by prophylactic proctocolectomy, surveillance until 40 years of age followed by subtotal colectomy, surveillance until 50 years of age followed by prophylactic proctocolectomy, surveillance until 50 years of age followed by subtotal colectomy, surveillance and proctocolectomy if an adenomatous polyp is found, surveillance and subtotal colectomy if an adenomatous polyp is found, surveillance and proctocolectomy if invasive cancer is diagnosed, surveillance and subtotal colectomy if invasive cancer is diagnosed, surveillance and segmental resection if invasive cancer is diagnosed, and no surveillance and segmental resection if invasive cancer is diagnosed. Figure 2 shows schematic representations of 2 of these strategies. Model outcomes were life expectancy and quality-adjusted life expectancy. Figure 2. Schematic representation of surveillance and colectomy if adenoma is found. Top. Bottom. Data Sources and Assumptions The probabilities and sources used in the model are listed in Table 1. The risk for colorectal cancer in mutation carriers was based on observed risks of colorectal cancer in a study of 210 carriers of an hMSH2 or hMLH1 mutation [20]. Mean risks for colorectal cancer among men and women in this study and in our baseline analysis were 31.5% by 40 years of age, 54.5% by 50 years of age, 63.0% by 60 years of age, and 87.5% by 75 years of age [20]. Age-specific incidence rates beyond 75 years of age were based on data from the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) Program [21], resulting in a lifetime risk for colorectal cancer of 88.2%. The lifetime risk for a second primary colorectal cancer was 45% [38]. Colorectal cancers in patients with hereditary nonpolyposis colorectal cancer who do not undergo regular surveillance were assumed to follow the same stage distribution as population rates, obtained from the SEER Program: 39% for localized cancer, 40% for regional cancer, and 21% for distant cancer [21]. Table 1. Input Variables Used in Baseline Analyses and Ranges of Sensitivity Analyses Performed Because no long-term follow-up studies of patients with hereditary nonpolyposis colorectal cancer undergoing colectomy have been published, we relied on studies of patients with familial adenomatous polyposis. Long-term follow-up of patients with familial adenomatous polyposis who have undergone proctocolectomy has shown that colorectal cancer in persons who were cancer-free at the time of surgery is rare [39-41]. In theory, prophylactic proctocolectomy eradicates all large-bowel mucosa at risk for colorectal cancer [42]. A prophylactic proctocolectomy was thus assumed to be 100% protective against colorectal cancer in the baseline analysis. The risk for colorectal cancer after subtotal colectomy with ileorectal anastomosis in patients with familial adenomatous polyposis ranges from 3.6% to 32% [22-25]. On the basis of these studies, prophylactic subtotal colectomy was assumed to result in an 80% reduction in lifetime risk for colorectal cancer in carriers of a mutation for hereditary nonpolyposis colorectal cancer (resulting in a lifetime risk for colorectal cancer of 17.5%). The stage-specific mortality rate associated with colorectal cancer was equal to that associated with resection alone or colectomy at the time of cancer diagnosis [39]; however, the risk for a second primary colorectal cancer was reduced by 80% with subtotal colectomy and by 100% with proctocolectomy. We assumed a perioperative mortality rate of 0.4% to 5.6% (depending on age) for persons undergoing prophylactic colectomy [26-28] and 0.8% to 11.2% (depending on age) for surgical resection of colorectal cancer [28, 29]. The largest prospective, controlled study of hereditary nonpolyposis colorectal cancer found that surveillance resulted in a 62% decrease in risk for colorectal cancer [30]. On the basis of this information, we used a constant percentage reduction each year so that the predicted lifetime risk was reduced by 62%. All colorectal cancer was assumed to be diagnosed at a localized stage (Dukes stage A or B1), as was the case in the largest trial of colonoscopic surveillance in the general population (the National Polyp Study [13, 31]) and in patients with hereditary nonpolyposis colorectal cancer who undergo surveillance [30, 33]. The mortality rate associated with endoscopic surveillance was 0.02%, based on several large studies of complications associated with endoscopic procedures [34-37]. Age- and sex-specific mortality estimates were obtained from U.S. life tables [43]. In our baseline analysis, we assumed that stage-specific colorectal canc