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.

Chemoprevention of hereditary colon cancers: time for new strategies.

Colorectal cancer (CRC) is potentially preventable. Chemoprevention, a focus of research for the past three decades, aims to prevent or delay the onset of cancer through the regression or prevention of colonic adenomas. Ideal pharmacological agents for chemoprevention should be cheap and nontoxic. Although data indicate that aspirin can reduce the risk of CRC in the general population, the highest return from chemopreventive strategies would be expected in patients with the highest risk of developing the disease, particularly those with a defined hereditary predisposition. Despite compelling data showing that a large number of chemopreventive agents show promise in preclinical CRC models, clinical studies have yielded conflicting results. This Review provides a historical and methodological perspective of chemoprevention in familial adenomatous polyposis and Lynch syndrome, and summarizes the current status of CRC chemoprevention in humans. Our goal is to critically focus on important issues of trial design, with particular attention on the choice of appropriate trial end points, how such end points should be measured, and which patients are the ideal candidates to be included in a chemopreventive trial.

Population-Based Lynch Syndrome Screening by Microsatellite Instability in Patients ≤50: Prevalence, Testing Determinants, and Result Availability Prior to Colon Surgery.

OBJECTIVES: As there are no US population-based studies examining Lynch syndrome (LS) screening frequency by microsatellite instability (MSI) and immunohistochemistry (IHC), we seek to quantitate statewide rates in patients aged ≤50 years using data from a Centers for Disease Control and Prevention-funded Comparative Effectiveness Research (CER) project and identify factors associated with testing. Screening rates in this young, high-risk population may provide a best-case scenario as older patients, potentially deemed lower risk, may undergo testing less frequently. We also seek to determine how frequently MSI/IHC results are available preoperatively, as this may assist with decisions regarding colonic resection extent. METHODS: Data from all Louisiana colorectal cancer (CRC) patients aged ≤50 years diagnosed in 2011 were obtained from the Louisiana Tumor Registry CER project. Registry researchers and physicians analyzed data, including pathology and MSI/IHC. RESULTS: Of the 2,427 statewide all-age CRC patients, there were 274 patients aged ≤50 years, representing health care at 61 distinct facilities. MSI and/or IHC were performed in 23.0% of patients. Testing-associated factors included CRC family history (P<0.0045), urban location (P<0.0370), and care at comprehensive cancer centers (P<0.0020) but not synchronous/metachronous CRC or MSI-like histology. Public hospital screening was disproportionately low (P<0.0217). Of those tested, MSI and/or IHC was abnormal in 21.7%. Of those with abnormal IHC, staining patterns were consistent with LS in 87.5%. MSI/IHC results were available preoperatively in 16.9% of cases. CONCLUSIONS: Despite frequently abnormal MSI/IHC results, LS screening in young, high-risk patients is low. Provider education and disparities in access to specialized services, particularly in underserved populations, are possible contributors. MSI/IHC results are infrequently available preoperatively.

Chemoprevention of colorectal cancer: systematic review and economic evaluation.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer in the UK: incidence increases with age, median age at diagnosis being over 70 years. Approximately 25% of cases occur in individuals with a family history of CRC, including 5% caused by familial adenomatous polyposis (FAP) or hereditary non-polyposis CRC (HNPCC). Most develop from adenomatous polyps arising from the intestine lining. Individuals with these polyps undergo polypectomy and are invited for endoscopic surveillance. Screening via faecal occult blood testing has been rolled out across the UK. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of drug and micronutrient interventions for the prevention of CRC and/or adenomatous polyps. Interventions considered include: non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and cyclo-oxygenase-2 (COX-2) inhibitors; folic acid; calcium; vitamin D and antioxidants (including vitamin A, vitamin C, vitamin E, selenium and beta-carotene). Chemoprevention was assessed in the general population, in individuals at increased risk of CRC, and in individuals with FAP or HNPCC. DATA SOURCES: A systematic review identified randomised controlled trials (RCTs) assessing drug and nutritional agents for the prevention of CRC or adenomatous polyps. A separate search identified qualitative studies relating to individuals' views, attitudes and beliefs about chemoprevention. MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, CINAHL, the Cochrane Database of Systematic Reviews, Cochrane CENTRAL Register of Controlled Trials, DARE, NHS-EED (NHS Economic Evaluation Database), HTA database, Science Citation Index, BIOSIS previews and the Current Controlled Trials research register were searched in June 2008. Data were extracted by one reviewer and checked by a second. REVIEW METHODS: The synthesis methods used were systematic review and meta-analysis for RCTs and qualitative framework synthesis for qualitative studies. A health economic model was developed to assess the cost-effectiveness of chemoprevention for two populations with different levels of risk of developing CRC: the general population and an intermediate-risk population. RESULTS: The search identified 44 relevant RCTs and six ongoing studies. A small study of aspirin in FAP patients produced no statistically significant reduction in polyp number but a possible reduction in polyp size. There was a statistically significant 21% reduction in risk of adenoma recurrence [relative risk (RR) 0.79, 95% confidence interval (CI) 0.68 to 0.92] in an analysis of aspirin versus no aspirin in individuals with a history of adenomas or CRC. In the general population, a significant 26% reduction in CRC incidence was demonstrated in studies with a 23-year follow-up (RR 0.74, 95% CI 0.57 to 0.97). Non-aspirin NSAID use in FAP individuals produced a non-statistically significant reduction in adenoma incidence after 4 years of treatment and follow-up and reductions in polyp number and size. In individuals with a history of adenomas there was a statistically significant 34% reduction in adenoma recurrence risk (RR 0.66, 95% CI 0.60 to 0.72) and a statistically significant 55% reduction in advanced adenoma incidence (RR 0.45, 95% CI 0.35 to 0.58). No studies assessed the effect of non-aspirin NSAIDs in the general population. There were no studies of folic acid in individuals with FAP or HNPCC. There was no significant effect of folic acid versus placebo on adenoma recurrence (RR 1.16, 95% CI 0.97 to 1.39) or advanced adenoma incidence in individuals with a history of adenomas. In the general population there was no significant effect of folic acid on risk of CRC (RR 1.13, 95% CI 0.77 to 1.64), although studies were of relatively short duration. Calcium use by FAP patients produced no significant reduction in polyp number or disease progression. In individuals with a history of adenomas there was a statistically significant 18% reduction in risk of adenoma recurrence (RR 0.82, 95% CI 0.69 to 0.98) and a non-significant reduction in risk of advanced adenomas (RR 0.77, 95% CI 0.50 to 1.17). In the general population there was no significant effect of calcium on risk of CRC (RR 1.08, 95% CI 0.87 to 1.34), although studies were of relatively short duration. There were no studies of antioxidant use in individuals with FAP or HNPCC, and in individuals with a history of adenomas no statistically significant differences in relative risk of adenoma recurrence were found. In the general population there was no difference in incidence of CRC (RR 1.00, 95% CI 0.88 to 1.13) with antioxidant use compared with no antioxidant use. Twenty studies reported qualitative findings concerning chemoprevention. People are more likely to use NSAIDs if there is a strong perceived need. Perceptions of risk and benefit also influence decision-making and use. People have fewer concerns about using antioxidants or other supplements, but their perception of the benefits of these agents is less well-defined. The model analysis suggested that the most cost-effective age-range policy in the general population would be to provide chemoprevention to all individuals within the general population from age 50 to 60 years. The use of aspirin in addition to screening within the general population is likely to result in a discounted cost per life-year gained of around 10,000 pounds and a discounted cost per quality-adjusted life-year (QALY) gained of around 23,000 pounds compared with screening alone. In the intermediate-risk group the most economically viable age-range policy would be to provide chemoprevention to individuals following polypectomy aged 61 to 70 years. Calcium is likely to have a discounted cost per QALY gained of around 8000 pounds compared with screening alone. Although aspirin in addition to screening should be more effective and less costly than screening alone, under the current assumptions of benefits to harms of aspirin and calcium, aspirin is expected to be extendedly dominated by calcium. LIMITATIONS: Whilst a number of studies were included in the review, the duration of follow-up was generally insufficient to detect an effect on cancer incidence. Given the uncertainties and ambiguities in the evidence base, the results of the health economic analysis should be interpreted with caution. CONCLUSIONS: Aspirin and celecoxib may reduce recurrence of adenomas and incidence of advanced adenomas in individuals with an increased risk of CRC and calcium may reduce recurrence of adenomas in this group. COX-2 inhibitors may decrease polyp number in patients with FAP. There is some evidence for aspirin reducing the incidence of CRC in the general population. Both aspirin and NSAIDs are associated with adverse effects so it will be important to consider the risk-benefit ratio before recommending these agents for chemoprevention. The economic analysis suggests that chemoprevention has the potential to represent a cost-effective intervention, particularly when targeted at intermediate-risk populations following polypectomy.

Genetics: what's it got to do with family health care?

Genetics is an important contributory factor in many medical conditions. Having an understanding of the genetic basis of diseases can therefore be helpful in identifying and supporting people who have, or are at risk of having, a genetic condition. Most of the current practical applications relate to conditions which are known to have a definite mode of inheritance (for instance cystic fibrosis or familial hypercholesterolaemia) or which are due to chromosomal anomalies (such as Down syndrome). Current research projects are attempting to identify and understand the genetic factors associated with common diseases (such as diabetes and Crohn's disease) but it will be some time before these are likely to be useful clinically. Key skills in the delivery of a holistic family practice service include being able to collect a genetic family history, identifying people at risk and knowing how to refer to specialist services.

Exploring the potential chemopreventative effect of aspirin and rofecoxib on hereditary nonpolyposis colorectal cancer-like endometrial cancer cells in vitro through mechanisms involving apoptosis, the cell cycle, and mismatch repair gene expression.

Women in hereditary nonpolyposis colorectal cancer (HNPCC) families have up to a 71% lifetime risk for developing endometrial cancer (EC). This compares to the female lifetime risk for colorectal cancer (CRC) in HNPCC of 60%. The basis of HNPCC is an inherited mutation in a mismatch repair gene (MMR). Aspirin and COX2 inhibitors seem to have a chemoprotective effect on CRC in the general population and are the subject of prospective clinical studies in patients at high risk for CRC including HNPCC. There is no evidence that these agents have any protective effect against EC in the general population. This study investigated the effect of aspirin and a COX2 inhibitor (rofecoxib) on an HNPCC EC cell line model (Ishikawa) by assessing the effect on proliferation, apoptosis, the cell cycle, and MMR gene expression. Aspirin inhibits EC cell proliferation by inducing apoptosis and changes in the cell cycle. This effect is not mediated by changes in MMR gene (hMSH2) expression as assessed by quantitative reverse transcription-polymerase chain reaction. Rofecoxib inhibits EC cell proliferation; this did not appear to be mediated by induction of apoptosis, by alterations of the cell cycle, or by changes in MMR gene expression.

Current approaches in familial colorectal cancer: a clinical perspective.

Individuals with a family history of colorectal cancer or colorectal adenomas have an increased risk for colorectal cancer. When no hereditary syndrome is evident, screening is based on empiric risk estimates. The risk is greatest for individuals with specific inherited cancer-predisposing disorders. When conditions such as familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer are diagnosed, specific neoplasm risk estimates can usually be performed based on advances in molecular genetics. These estimates lead to more straightforward and cost-effective approaches to surveillance and management. The National Comprehensive Cancer Center Network (NCCN) and other groups have provided detailed guidelines for evaluating patients based on recognition of clinical syndrome characteristics, followed by appropriate genetic counseling, genetic testing, and optimal surveillance. The NCCN guidelines are used as a frame of reference for this discussion of selected recent advances in human cancer genetics as they apply to clinical practice.

[Cancer prevention in familial cancer].

We established a protocol for and will conduct an interventional randomized controlled trial for the prevention of colorectal cancer. The subjects will be 100 patients with hereditary non-polyposis colorectal cancer. Two regimens were formulated for the prevention of colorectal cancer. Regimen A is dietary guidance and ingestion of aged garlic extract (AGE) capsules, and regimen B is dietary guidance and non-function capsules. The main end point of the trial is number and size of colorectal adenomas after 2 years. Subject recruiting was started in March, 2002. The trial will be completed in September, 2005.

Genetic screening for colorectal cancer and intervention.

There is a complex interaction between environmental/dietary factors and genetics underlying the pathogenesis of colon carcinogenesis. Little data exist concerning the impact of diet on the phenotypic expression of genetically linked colon cancer. As a result, it has been difficult to develop rationally designed dietary intervention studies in first-degree relatives of patients with established familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC) and other familial colon cancer syndromes. Only 2 double-blinded, placebo-controlled trials have been published concerning the use of preventive strategies in patients with genetically inherited colorectal cancer syndromes, both in patients with FAP. One study evaluated the effects of vitamin C plus vitamin E with or without a high-dose wheat bran fiber supplement on the recurrence of rectal adenomas. Over a 48-month intervention period, only the wheat bran fiber intervention significantly reduced polyp growth. A second study reported that intervention with the NSAID sulindac for 9 months in young patients with FAP resulted in a significant reduction in both polyp number and size in the rectosigmoid colon. All of the large-scale (i.e., >500 randomized participants) phase III nutrient or chemopreventive agent intervention studies thus far have targeted participants with a history of non-familial, sporadic colorectal adenomas. Current clinical adenoma trials do not measure whether the regimen being tested can prevent genotoxic events occurring in early stages of abnormal cell development that contribute to the eventual formation of adenomas nor whether the agent(s) can inhibit events occurring during the progression of adenomas to carcinomas. Therefore, future clinical trial designs may have to consider (i) lengthening the clinical trial period before adenomas develop, (ii) testing at early patient ages and/or (iii) measuring the growth of adenomas as they progress to carcinomas.

Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer.

BACKGROUND/AIMS: The inherited susceptibility to hereditary nonpolyposis colorectal cancer (HNPCC) provides an opportunity for secondary prevention of colorectal cancer (CRC) in family members who are at 50% lifetime risk. The aim of this study was to evaluate the effectiveness of long-term screening during a 10-year period. METHODS: The CRC and death rates were compared between two groups of asymptomatic at-risk members of 22 families with HNPCC: 133 subjects screened at 3-year intervals by colonoscopy or barium enema and sigmoidoscopy and 118 control subjects without screening. The screening was complete in 118 subjects (89%), whereas 18 control subjects (15%) had screening examinations outside of the study. RESULTS: CRC occurred in 6 study subjects (4.5%) and in 14 controls (11.9%; P = 0.03), a difference of 7.4% in favor of the study group, which corresponds to a reduction by 62% that is presumably because of polypectomies. The tumor stage was more favorable in the screening group with no deaths caused by CRC compared with 5 of 14 cases in controls. Overall, there were 6 and 12 deaths within the 10-year period in the study and control groups, respectively (P = 0.08). CONCLUSIONS: The 3-year interval screening more than halves the CRC rate in at-risk members of families with HNPCC and seems to prevent CRC deaths.

Screening for hereditary non-polyposis colorectal cancer: a study of 22 kindreds in The Netherlands.

PURPOSE: Identification of the hereditary non-polyposis colorectal carcinoma syndrome (HNPCC) is a basis for secondary prevention. The objectives of this study are to investigate the natural history of HNPCC and to assess the effect of screening. PATIENTS AND METHODS: Screening for colorectal carcinoma was performed in 22 HNPCC families (colonoscopy or double-contrast barium enema and sigmoidoscopy). The patients were subdivided into two groups. Group A comprised patients with colorectal cancer who were referred because they were symptomatic. Group B included family members of these patients who were found to have a colorectal lesion by screening. We compared these groups with respect to the stage of tumor growth. RESULTS: Histologic examination of the tumors in Group A (87 patients) revealed Dukes A carcinomas in six patients, Dukes B carcinomas in 37, Dukes C carcinomas in 21, and Dukes D carcinomas in 10 patients (classification unknown in 13 patients). In Group B (20 patients), adenoma was found in 14 and carcinoma in six patients (Dukes A in two and Dukes B in four patients). A total of 93 patients, including those whose tumors were detected by screening, had a colorectal carcinoma. The age at diagnosis ranged from 24 to 81 years (mean age: 46 years). The location of the colonic tumors was proximal in 60 percent. Multiple primary tumors were found in 26 percent. CONCLUSION: These results suggest that screening leads to the early detection of colorectal carcinomas and adenomas in asymptomatic members of HNPCC families. Screening should be initiated at the age of 20 and continued during the life of the individual. Careful examination of the right colon is indicated because of the frequent occurrence of tumors in the proximal colon. A subtotal colectomy is indicated at the time of diagnosis of the initial colon cancer because of the risk of multiple primary tumors.