Cost-effectiveness of preventive aspirin use and intensive downstaging polypectomy in patients with familial adenomatous polyposis: A microsimulation modeling study.

OBJECTIVE: Although there is increasing evidence to suggest the cost-effectiveness of aspirin use to prevent colorectal cancer (CRC) in the general population, no study has assessed cost-effectiveness in patients with familial adenomatous polyposis (FAP), who are at high risk of developing CRC. We examined the cost-effectiveness of preventive use of low-dose aspirin in FAP patients who had undergone polypectomy in comparison with current treatment practice. DESIGN: We developed a microsimulation model that simulates a hypothetical cohort of the Japanese population with FAP for 40 years. Three scenarios were created based on three intervention strategies for comparison with no intervention, namely intensive downstaging polypectomy (IDP) of colorectal polyps at least 5.0 mm in diameter, IDP combined with low-dose aspirin, and total proctocolectomy with ileal pouch-anal anastomosis (IPAA). Cost-effective strategies were identified using a willingness-to-pay threshold of USD 50,000 per QALY gained. RESULTS: Compared with no intervention, all strategies resulted in extended QALYs (21.01-21.43 QALYs per individual) and showed considerably reduced colorectal cancer mortality (23.35-53.62 CRC deaths per 1000 individuals). Based on the willingness-to-pay threshold, IDP with low-dose aspirin was more cost-effective than the other strategies, with an incremental cost-effectiveness ratio of $57 compared with no preventive intervention. These findings were confirmed in both one-way sensitivity analyses and probabilistic sensitivity analyses. CONCLUSION: This study suggests that the strategy of low-dose aspirin with IDP may be cost-effective compared with IDP-only or IPAA under the national fee schedule of Japan.

Chemoprevention of colorectal neoplasia.

BACKGROUND: Colorectal cancer is a common and often fatal malignancy. Currently, the modifications that alter disease outcome include early symptom recognition, population screening as well as improved surgical and adjuvant treatments. Preventative strategies have been limited with little evidence that lifestyle changes significantly alter risk. There is however a growing awareness of a potential role for chemoprevention in some patient groups. This study aimed to review the literature associated with chemoprevention in colorectal cancer. METHODS: An electronic literature search of MEDLINE and Embase databases was performed on PubMed for studies detailing the use of chemoprevention agents in colon and rectal cancer. The search was limited to clinical trials on adult humans (>16 years of age) published in English since 1990. RESULTS: The strongest evidence is for non-steroidal anti-inflammatory drugs slowing polyp progression, notably Sulindac and aspirin in patients with familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, respectively. There is also increasing evidence that continuing use of low-dose aspirin reduces long-term incidence of colorectal cancers. Cyclooxygenase 2 inhibitors also have a potential role but cardiac toxicity currently limits their use. Folic acid, statins, antioxidants, calcium and 5-aminosalicylic acid lack evidence to support their use at present. CONCLUSIONS: Currently, there is not enough evidence to support the implementation of a chemopreventative agent for general use. However, there appears to be a role for aspirin in selected subgroups.

Global quantitative assessment of the colorectal polyp burden in familial adenomatous polyposis by using a web-based tool.

BACKGROUND: Accurate measures of the total polyp burden in familial adenomatous polyposis (FAP) are lacking. Current assessment tools include polyp quantitation in limited-field photographs and qualitative total colorectal polyp burden by video. OBJECTIVE: To develop global quantitative tools of the FAP colorectal adenoma burden. DESIGN: A single-arm, phase II trial. PATIENTS: Twenty-seven patients with FAP. INTERVENTION: Treatment with celecoxib for 6 months, with before-treatment and after-treatment videos posted to an intranet with an interactive site for scoring. MAIN OUTCOME MEASUREMENTS: Global adenoma counts and sizes (grouped into categories: <2 mm, 2-4 mm, and >4 mm) were scored from videos by using a novel Web-based tool. Baseline and end-of-study adenoma burden results were summarized by using 5 models. Correlations between pairs of reviewers were analyzed for each model. RESULTS: Interobserver agreement was high for all 5 measures of polyp burden. Measures that used both polyp count and polyp size had better interobserver agreement than measures based only on polyp count. The measure in which polyp counts were weighted according to diameter, calculated as (1) × (no. of polyps <2 mm) + (3) × (no. of polyps 2-4 mm) + (5) × (no. of polyps >4 mm) had the highest interobserver agreement (Pearson r = 0.978 for two gastroenterologists, 0.786 and 0.846 for the surgeon vs each gastroenterologist). Treatment reduced the polyp burden by these measurements in 70% to 89% of patients (P < .001). LIMITATIONS: Phase II study. CONCLUSION: This novel, Web-based polyp scoring method provides a convenient and reproducible way to quantify the global colorectal adenoma burden in FAP patients and a framework for developing a clinical staging system for FAP.

Recognition and management of hereditary colorectal cancer syndromes.

Over 1,900 colorectal tumors will arise in association with a hereditary colorectal cancer syndrome in Spain in 2009. The genetic defects responsible for the most common syndromes have been discovered in recent years. Genetic testing helps diagnose affected individuals and allows identification of individuals at-risk. Colonoscopy and prophylactic colectomy decrease colorectal cancer incidence and overall mortality in patients with hereditary colon cancer. Extracolonic tumors are frequent in these syndromes, so specific surveillance strategies should be offered.

Celecoxib: a new option in the treatment of arthropathies and familial adenomatous polyposis.

The discovery of the two isoenzymes of cyclooxygenase (COX) has recently lead to the development and clinical introduction of specific inhibitors of cyclooxygenase-2 (COX-2), such as celecoxib, onto the market. Celecoxib is an effective anti-inflammatory, analgesic and antipyretic agent therapeutically utilised in the management of osteoarthritis and rheumatoid arthritis. In addition, celecoxib has some novel therapeutic and pharmacological activities. Celecoxib inhibits anti-apoptotic kinase activation and is the first specific COX-2 inhibitor to be marketed for familial adenomatous polyposis, an inheritable predisposition for colorectal cancer. Celecoxib is not without gastrointestinal (GI) side effects but demonstrates markedly reduced GI ulceration in clinical trials when compared to traditional non-specific non-steroidal anti-inflammatory drugs (NSAIDs). The specific COX-2 inhibitors each have distinctive pharmacokinetic properties. Celecoxib can be given either once or twice daily. Racial differences in drug disposition, and pharmacokinetic changes in elderly patients, patients with chronic renal insufficiency and patients with mild to moderate hepatic impairment, are evident with celecoxib. Despite the specific action of these drugs, there remains the potential for significant drug interactions. Celecoxib has demonstrated interactions with fluconazole, lithium and warfarin. Increased clinical vigilance should be maintained when co-prescribing medications with celecoxib until further clinical experience is gained. Celecoxib represents a major therapeutic advance in terms of GI safety. However, long-term safety in other organ systems, safety with concomitant drug administration, and pharmacoeconomic benefits still remain to be proven.

A generalized estimating equations approach for testing ordered group effects with repeated measurements.

In repeated measures studies, we are often interested in comparing group effects in which groups are associated with a certain order relation. We propose testing procedures for ordered group effects using the generalized estimating equations (GEE) approach of Liang and Zeger (1986, Biometrika 73, 13-22). The order-constrained GEE estimators of group effects are approximated by the isotonic regression of the unconstrained GEE estimators. Based on these constrained estimators, we construct test statistics for detecting ordered group effects. The limiting distributions of the test statistics are mixtures of chi-square distributions. A Monte Carlo experiment shows improved performances of the proposed tests over the usual chi-square tests in detecting ordered group effects. The proposed test procedures are illustrated by familial polyposis supplementation trial data.