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SCREENING FOR COLORECTAL CANCER
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ONCOLOGY
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SCREENING FOR COLORECTAL CANCER Michelle A. Jediiak, MD and Timothy T. Nostrant, MD
The last decade has seen an exponential rise in our understanding of the epidemiology, cause and natural course of colorectal cancer (CRC). A number of randomized, controlled studies evaluating cancer screening methods have recently been completed and published. Results of these studies have enabled clinicians to make educated decisions and recommendations when counseling their patients as to the various screening modes available and in choosing optimal screening programs. This article will review the most current information on CRC including epidemiology, clinical features, available screening methods and their respective values, and will offer recommendations on effective implementation in clinical practice.
EPIDEMIOLOGY
CRC is the second leading cause of cancer death, representing approximately 14% of all cancer-related mortality, and the third most frequently diagnosed malignancy in the United States, following only lung and prostate cancer.*Risk factors for CRC include advanced age, several life-style factors, personal or family history of colorectal adenoinatous polyps or cancer, and inflammatory bowel disease, as well as several hereditary syndromes such as Lynch syndrome and familial adenomatous polyposis (FAP). CRC Risk Factors Age > 50 High fat/low calcium diets Low vegetable intake Obesity Smoking Personal/family history of polyps/CRC From the Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, Michigan PRIMARY CARE VOLUME 25 .NUMBER 2 IUNE 1998 9
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Inflammatory bowel disease (CUC, Crohn's, colitis) Hereditary syndromes Familial adenomatous polyposis (FAP) Hereditary nonpolyposis colon cancer Isolated colon cancer (Lynch 1) Multiple cancers Uterine Ovarian Breast Colon Gastric Pancreatic Thyroid Lung There is wide geographic variation in CRC incidence, with industrialized nations being at greater risk than developing countries.*"Interestingly, these differences do not appear to be solely genetically determined since migration from a low- to high-risk area is associated with increased rates of CRC.3nThis finding supports an environmental or dietary role in the causation of CRC. CRC occurs with slightly higher frequency in African-Americans than in whites, with higher mortality in native Alaskans6'; incidence in men and women is approximately Finally there is evidence that the regular use of nonsteroidal anti-inflammatory drugs may decrease risk for colorectal adenomas as well as cancer. Giardiello et a1 found that sulindac given twice daily for 9 months decreased both the size and number of colorectal polyps in patients with familial adenomatous polyposis.26Similarly, a prospective cohort study by Giovannucci et a1 showed that patients using two or more aspirin per week had a 32% reduction in risk for colorectal cancer and a 28% reduction in risk for colorectal adenomas compared with nonusers.27
CLINICAL MANIFESTATIONS
Colorectal cancer may present in a variety of ways and depends to some degree on the size and location of the tumor. Cancers of the proximal colon can grow large and often bleed for a prolonged period prior to detection, resulting in iron deficiency, anemia, and sometimes hematochezia. Local invasion of adjacent organs can result in pain or may produce symptoms specific to the organ that it invades. For example, invasion of the bladder may cause pneumaturia. Occasionally, tumor growth through the muscularis propria will result in perforation and the patient will present with an acute abdomen. Since the lumen of the transverse, descending, and sigmoid colons are narrow relative to the cecum and ascending colon, these are common sites for obstructing tumors. Patients with obstruction may present with abdominal distention, pain, nausea, vomiting, change in bowel habits or in stool diameter (e.g., pencil stools). Obstruction as a presenting sign suggests the presence of a large tumor, and is associated with significantly reduced survival.83Finally, patients may present with nonspecific symptoms such as anorexia or weight loss. Often colorectal tumors do not prbduce symptoms until late in the natural course of the disease. Therefore, a majority of patients whose first evaluation is at the time of clinical symptoms will have advanced cancer and likely will die of their disease. This is supported by the findings of Hardcastle et a1 who prospectively evaluated patients for CRC with and without screening fecal occult blood testing (FOBT). This study followed more than 150,000 patients over a mean in-
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terval of 7.8 years and found that individuals who did not undergo evaluation until the time of symptom presentation were significantly more likely to have advanced stage tumors (Dukes' C or D) and die from colorectal cancer than screened individual^.^^ It is crucial, therefore, that screening strategies be designed to detect disease prior to clinical manifestations and at earlier, treatable stages. RATIONALE FOR SCREENING
Currently, many Americans are not screened for CRC; information from the National Health Interview Survey indicates that only 17%of people over 50-yearsold underwent fecal occult blood testing (FOBT) in 1991 and only 9.4%underwent sigmoidoscopy in the prior three year^.^,'^ Uncertainty about screening methods, frequency of testing, populations to be screened and the cost-effectiveness of various testing methods has precluded agreement among health care professionals as to screening for this prevalent and potentially treatable disease. In 1994, the Federal Agency for Health Care Policy and Research (AHCPR) joined with the American Gastroenterology Association (AGA) in a combined effort to critically review the evidence on CRC and to develop guidelines based on their findings. These guidelines were based on information from 350 key articles selected from a MEDLINE search of the scientific literature and were published in a detailed article in the February 1997 issue of Gastroenter~logy.~' Screening refers to tests that identify persons at-risk for a particular disease, but without symptoms, signs or easily identifiable risk factors. Screening is deemed effective and valuable when a number of conditions are met. The disease must be common and associated with significant morbidity or mortality. CRC is quite common, with an estimated lifetime risk of 6% in asymptomatic, average risk individuals. Available screening tests must have adequate sensitivity in detecting early stage disease, must be acceptable to patients and must be available in clinical practice, The various screening tests for CRC that are currently available have sensitivities ranging from 40% to 90%.Further, few polyps advance to cancer (approximately2.5 per 1000 polyps per year),Z3and the progression from adenomatous polyp to carcinoma occurs slowly over many years, although the precise time interval for transformation is unknown. Diagnosis and treatment at an earlier disease stage must provide improved outcome over detection through clinical presentation at a later disease stage. In the case of CRC, it is well established that advanced tumor stage is associated with decreased survival (33%for Dukes' Stage C at 5 years versus 64% to 85% for Dukes' Stage A or B at 5 years).93Multiple controlled trials have established with reasonable certainty that detecting early-stage CRC is possible with appropriate screening method^.^^,^^,^^,^^,^^,^^ Finally, the screening test should be cost-effective and have acceptably low risk when compared to potential benefit. Several cost-effectiveness analyses have shown that FOBT, flexible sigmoidoscopy, double contrast barium enema and colonoscopy can cost less than $20,000 per year of quality life saved, a figure comparable or better than that for other commonly screened-for cancers such as breast or cervical It is estimated that the cost per person (entered at 50-yea:s-oldf will range from $250 to $1200 depending on screening interval, method used, and billing costs for a particular procedure in a given geographic area.22,46 CRC SCREENING IN PERSONS AT AVERAGE RISK
Persons over the age of 50 without a history of inflammatory bowel disease or genetic syndromes associated with CRC, and without a personal or family
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history of CRC or adenomatous polyps, are defined as those at average risk of developing CRC. Individuals with symptoms suggestive of polyps or colorectal cancer or with a history of gastrointestinal bleeding are not candidates for screening and should be offered appropriate diagnostic examinations. Based on a critical review of the available literature, a multidisciplinary panel representing the AGA with the endorsement of the American Cancer Society, the American College of Gastroenterology, the American Society of Colon and Rectal Surgeons and others, have recommended that screening in average-risk individuals begin at the age of 50 and use either FOBT, flexible sigmoidoscopy, a combination of FOBT and sigmoidoscopy, double contrast barium enema (DCBE), or colono~copy.~~ (Table 1)
Fecal Occult Blood Testing Stool guaiac tests test for peroxidase activity using a colorless indicator, guaiac gum, that is oxidized to a pigmented quinone in the presence of peroxidase and hydrogen peroxide. Hemoglobin has pseudoperoxidase activity, therefore bleeding polyps or cancers within the colon will give a positive reaction. Sensitivity of guaiac-based tests are closely related to the amount of blood in the stool. Stool hemoglobin concentrations less than 2 mL/g of stool usually result in a negative Blood loss must be in the range of 10 mL per day to produce a consistently positive result on FOBT. Additional factors may influence the sensitivity and specificity of the test, including rare red meats, turnips, horseradish (false positive), Vitamin C (false negative), and salicylates (false p~sitive).~’ There has been considerable debate as to the effect of oral iron on stool guaiac tests. Although oral iron probably does not cause false positive reactions or induce GI a study by McDonnell et a1 reported that the black pigment in stools of patients on iron supplements could be misinterpreted as positive.60Further, the length of storage may affect test sensitivity; one study showed decreased reaction intensity after 4 days and false negative reactions in 8 days.R4Rehydration improves sensitivity of testing at the cost of increased false positives.s1 When administered to asymptomatic populations, FOBTs are positive approximately 1%to 16% of the time?’ with reported sensitivities for cancer ranging from 38% to 96% depending on the test used as well as the size and location of t ~ m ~ r .Reported ~ ~ J ~specificities , ~ ~ range from 88% to 98%. A study by Allison et
Table 1. COLORECTAL CANCER SCREENING RECOMMENDATIONS Average-Risk Patient Onset of Screening Age
2
50
Screening Tests Fecal Occult Blood Test (FOBT) Flexible sigmoidoscopy (FS) FOBT/FS combination Air contrast barium enema Colonoscopy
Frequency Yearly Every 5 years
Other Recommendations Medicare will pay FOBT every year FS every 4 years
FS or FOBT (not both) Every 5-1 0 years Every 10 years
Air contrast barium enema with restrictions* Not colonoscopy
’Attending must attest in writing that ACBE is equal to or greater than FOBT or FS in a particular patient Single contrast BE can be ordered at attending discretion
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a1 compared the performance characteristics of three FOBTs (Hemoccult 11, Hemoccult I1 Sensa and Hemeselect) and found Hemoccult I1 Sensa had the highest sensitivity for carcinomas (79.4%)while Hemoccult I1 had the highest specificity (97.7%).' Overall, Hemeselect and a combination test in which Hemeselect was used to confirm positive Hemoccult I1 Sensa results provided the greatest positive predictive value in detecting colorectal carcinomas and polyps. When the colons of persons with positive test results are evaluated, colorectal cancers are found in 2% to 17% of patients7' To date, three randomized controlled studies, one case-control study and one nonrandomized controlled study have demonstrated a reduction in death from colorectal cancer in patients screened with FOBTs followed by colonoscopy in guaiac-positive i n d i v i d ~ a l s . ~ Strong, ~ ~ ~ ~ ~direct ~ ~ , ~evidence ~ , ~ " for the effectiveness of FOBT has prompted recommendations for annual screening over biannual screening based on results from the Minnesota Colon Cancer Control which showed a 33% reduction in mortality in annually screened patients and no significant reduction in mortality in patients screened every 2 years. Persons with a positive FOBT should undergo evaluation of the entire colon and rectum either with'colonoscopy or with double contrast barium enema, preferably coupled with flexible sigmoidoscopy. Compliance with FOBT varies widely between regions, patient populations and practitioners. Characteristics associated with increased compliance include female sex: higher socio-economic status2 more personal and family experiences with illness>b regular visits to a dentistbhand membership in a health maintenance organization (HMO).I3The role of the clinician in achieving compliance with a screening regimen is also significant.hsVarious compliance factors, coupled with the relatively modest reduction in mortality offered by FOBT in comparison with alternate means of screening, must be considered by the health care provider when choosing this as the standard screening technique for his or her practice.
Sigmoidoscopy
The standard sigmoidoscope employed in clinical practice is a flexible scope, 35-cm or-60 cm in length. Under optimal conditions, the 35-cm scope is able to reach only the proximal sigmoid colon, although the 60-cm scope routinely reaches the descending colon sometimes to the level of the splenic flexure and beyond. Prior to testing, the bowel is prepared using saline enemas or an oral cathartic solution. Patients generally are not sedated for the procedure because most patients experience only mild to moderate discomfort during the exam.21,92 The procedure typically lasts 10m to 15m, but performance time may vary depending on the skill and experience of the e n d o ~ c o p i s and t ~ ~the ~ ~adequacy ~~~ of the bowel preparation. Sigmoidoscopy offers important advantages over FOBT for CRC screening. It allows direct visualization of the bowel wall as well as the capacity to biopsy or remove suspicious lesions. The most serious potential complication of sigmoidoscopy is perforation of the colon, although this is rare, with rates ranging from one to three cases in 10,000 examinatioi~s.~~ Other rare complications include iatrogenic infection and bleeding postbiopsy. Sigmoidoscopic exams reaching the proximal end of the sigmoid colon have been shown to detect approximately 50% of colonic polyps and cancer^^^,^^ with approximately one-third to one-half occurring proximal to the area visualized in a standard p r o c e d ~ r e . ~Several , ~ ~ , ~case ~ , ~control ~ ~ t ~ d i have e ~ demonstrated ~ ~ , ~ ~ , ~ ~ a decrease in cancer related mortality in patients undergoing sigmoidoscopic screening, primarily with rigid sigmoidoscopy. Although a randomized controlled
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trial of flexible sigmoidoscopy for the prevention of CRC is currently in progress,” no such study has been published yet. Given that few polyps arise and progress to advanced cancer in less than 5 years and the findings from one study showing a protective effect against death from CRC by endoscopy of at least 6 current recommendations offer screening sigmoidoscopy at 5 year i n t e r v a l ~ Persons .~~ with polyps greater than I-cm in diameter and those with cancer on flexible sigmoidoscopy should undergo full colonoscopic examinations. Controversy exists over the work-up of patients with adenomatous polyps less than I-cm in diameter, but evidence suggests that approximately one-third of these patients will have additional adenomatous polyps in the proximal colon and an equal number of patients will have polyps in the proximal colon while having no polyps or nonneoplastic polyps in the distal colon,’736 No specific recommendations with regard to this population are made in the recently published AGA guideline^.^^ Factors that influence compliance with screening sigmoidoscopy are similar to those noted for FOBT and include female gender, higher income, routine health evaluations, older age and a family history of c a n ~ e r . ’ ~ , ~ ~ Combined FOBT and Sigmoidoscopy
Current guidelines support combined annual FOBT and sigmoidoscopy at 5 year intervals as an acceptable method of CRC screening, noting that sigmoidoscopy complements FOBT through increased sensitivity for detecting adenomatous polyps and cancers of the left Further, sigmoidoscopy provides an opportunity for identifying adenomatous polyps and for potentially reducing CRC, or at least detecting it an earlier stage. This recommendation is supported by a large, nonrandomized, controlled study in which patients were assigned to either FOBT with rigid sigmoidoscopy or rigid sigmoidoscopy alone.9oPatients in the combined screening group had an approximately 55% reduction in CRC mortality compared with the group receiving sigmoidoscopy alone. Barium Enema
Prior to undergoing barium enema, the bowel is prepared using a prescribed low-residue or liquid diet, usually taken on the day prior to the procedure, as well as laxatives or cathartic solutions on the evening prior to the test. Radiologic examination of the colon can be performed using either a single- or double-contrast technique. In single contrast studies, the entire colon is a filled with a liquid lowdensity barium suspension via a small tube inserted into the rectum approximately 3-cm to 4-cm. The examination is performed with palpation and various compression maneuvers under fluoroscopic monitoring. Radiographic images are obtained when barium reaches the cecum. In double contrast studies, a smaller volume of high density barium is instilled into the colon followed by insufflation of air. Although more difficult to perform and physician-intensive, double contrast barium enema (DCBE) is superior to single contrast studies in demonstrating fine mucosal lesions such as polyps and nonobstructing cancers.69Complications in barium enemas are rare; perforation, the most serious complication, occurs at a rate of 1 per 25,000 cases. Reported sensitivities of DCBE for colorectal cancer range from 70% to 95%; however, there exists an irreducible minimum error rate of approximately 5%40 that is largely caused by interpretation and suboptimal studies even in very experienced hands. Though insertion of barium is simple, instilling the correct quan-
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tities of the barium and air and providing appropriate compression requires time and skill on the part of a dedicated radiologist. If a high quality study is obtained, there can be difficulties in interpretation that are caused by patient anatomy or muscle spasm, and false positive readings caused by adherent stool or air bubbles. In addition, patients with an abnormality on DCBE likely will require colonoscopy, although very few colonoscopic findings require further evaluation with DCBE. Therefore, pretest probability of disease is very important in choosing between DCBE and colonoscopy. This is because colonoscopy, unlike DCBE, allows biopsy or snare excisions of lesions and DCBE does not. Nonetheless, DCBE is a safe, simple procedure with satisfactory patient acceptance and retains a useful role in CRC screening. With regard to cost-effectiveness, a recent review by Gelfandz5concluded that barium enema was the most cost-effective method of CRC screening, although others have found colonoscopy and barium enema to have comparable cost-effectiveness5~1z with actual cost varying according to procedure charges, work-up algorithms and frequency of screening employed. Some have recommended combined flexible sigmoidoscopy and DCBE as a screening technique, citing the added sensitivity of flexible sigmoidoscopy for lesions in the rectosigmoid C O ~ O ~ . * ~ Currently, there are no studies assessing optimal screening intervals of DCBE for CRC. Guidelines recommend DCBE, preferably with flexible sigmoidoscopy, every 5 to 10 years." Colonoscopy
Preparation for colonoscopy sometimes can begin days prior to the procedure with modifications in diet and medications. Patients with chronic constipation or those with a history of inadequate prep on previous exams often are placed on a liquid diet a day or two prior to the test. Persons on oral iron therapy are advised to stop the medication 4 to 5 days prior to colonoscopy, since iron may combine with vegetable residue changing the mucosal appearance of the colon and producing a sticky film that is difficult to clear. Aspirin, warfarin and other antiplatelet or anticoagulant drugs are held for 7 days prior to the test in order to reduce the risk of immediate or delayed bleeding in cases for which polypectomy is performed. One of any number of osmotic or isotonic cathartic solutions is administered to cleanse the bowel the evening prior to the examination. Even patients with a history of diarrhea or defunctionalized bowel will require some degree of preparation as stool residue in these patients can significantly obscure mucosal evaluation, though larger lesions are seldom missed. Generally, patients receive intravenous sedation at the time of colonoscopy, which provides pain control and amnestic benefits. In most centers, patients are monitored for cardiorespiratory complications throughout the procedure. The colonoscopic exam is performed using a high resolution flexible endoscope 15mm to 17mm in diameter and 165cm in length. The scope is introduced through the anus and advanced to the cecum while the endoscopist views tip progression via a full color video monitor. The procedure typically takes 20 to 30 minutes, but duration may vary with the skill of the examiner, patient anatomy, and ade-quacy of bowel preparation. Unlike any of the other screening methods previously reviewed, colonoscopy offers the ability to view the entire colon and to biopsy or remove any suspicious lesions through electrocautery with forceps or a wire snare. Colonic intubation to the cecum is achieved in over 90% of cases.54Incomplete exams should be followed with either barium enema or repeat colonoscopy. Although the accuracy of colonoscopy in detecting lesions greater than l-cm in size is 90% to 95%, it is estimated that smaller lesions are missed 10% to 25% of the
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time.'s,35,36,sn This is partly caused by blind spots including acute bends and flexures as well as poor preparation and redundant or mobile colons. Colonoscopy can produce vagally-mediated dysrhythmias, hypotension and hypoxia and is therefore contraindicated for weeks to months following myocardial infarction.6' Respiratory depression can occur secondary to sedation and many patients experience abdominal pain or discomfort caused by air insufflation during or after the examination. More serious complications include perforation (-1/1,000 exams), major hemorrhage (-3/1000 exams) and death (1 to 3/10,000 exams).28,3Y,39,5h,73,89 A study by Bat and colleagues7concluded that older patients are no more likely to experience complications than younger patients. Indirect evidence has shown that colonoscopy as a screening method for CRC reduces mortality, and a case-control study by Muller et a1 demonstrated that patients undergoing colonoscopy had a 39% reduction in CRC events over controls."3Current guidelines recommend screening colonoscopy be performed at 10year intervals." Though there are no studies that specifically address frequency of screening colonoscopy, this interval was chosen on the basis that the natural history of polyp growth in familial polyposis required ten years for the development of advanced lesions. In addition, sigmoidoscopy afforded protection from distal CRC for 10 years in case-controlled
CRC SCREENING IN PERSONS AT INCREASED RISK A number of factors can put an individual at risk for CRC; screening recommendations for these individuals are outlined in Table 2. Genetic Syndromes
Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disorder with an 80% to 100% penetrance"' resulting from a mutation in the APC gene on the long arm of chromosome 5.1° Actual mutations vary among affected kindreds, but the majority code for a truncated, inactive protein. The APC protein functions to regulate cell growth and therefore has a tumor suppressor role with mutation resulting in deregulation and occurrence of CRC at an early age. It is estimated that patients who inherit the mutated gene have a 50% chance of developing CRC by 16-years-of-age70and a nearly 100% risk of developing CRC by young adulthood. Men and women are affected equally and polyps are evenly distributed throughout the Variants of familial polyposis have been described with few polyps and late onset CRC. Once polyp formation has occurred, surveillance colonoscopy is no longer useful because of the multitude of polyps (averaging >lo00 in patients with fully expressed FAP) and consideration of total colectomy should be undertaken. Genetic testing by linkage analysis can be performed if blood from affected family members is available. In patients who are known gene carriers or are indeterminate carriers, flexible sigmoidoscopy to assess for gene expression should be initiated at puberty and performed annually thereafter. Detection of polyps should prompt referral for colectomy. Hereditary nonpolyposis colorectal cancer (HNPCC), commonly referred to as Lynch syndrome, is also an inherited autosomal dominant disease caused by mutations in DNA mismatch repair genes.s0The HNPCC gene displays high penetrance but age of presentation is variable. The diagnosis is primarily clinical with criteria (referred to as the Amsterdam criteria) developed by an international collaboration and is as follows: Three or more relatives with a verified colorectal
.
*Attending must attest in writing that ACBE is equal/greater than FOBT or Single contrast BE can be ordered at attending discretion. "Any first degree relative: parent, sibling, child. Multiple second/third degree relatives tGenetic testing has limitations Expert counseling crucial Sulindac (Glindoril) may be helpful in particular situations --Delay surgery (FAP, Gardner's) -Poor operative risk (FAP, Gardner's)
Gardner's syndrome
Familial adenomatous polyposis (FAP)
index case 10 years earlier than index case (usually adolescence) Same as FAP
10 years earlier than
After 7 years disease
Chronic ulcerative colitis
Hereditary colon cancer syndrome Hereditary nonpdyposis CRC (HNPCC)
After 7 years disease
Inflammatory Bowel Disease Crohn's colitis
FS in a particular patient
Colonoscopy
Colonoscopy
Colonoscopy
Colonoscopy
Colonoscopy
Colonoscopy
10 years earlier than
PersonaVFamily Hx polyps/CRC** index case
Screening Tests
Onset of Screening
Hight-Risk Patient
Table 2. COLORECTAL CANCER SCREENING RECOMMENDATIONS
Yearlyt
Every 1 to 2 years Yearly after age 40t Yearlyt
Yearly (>20 years of disease)
Every 1 to 2 years (<20 years of disease)
Every 3 to 5 years
Frequency
Other Recommendations
-
Colonoscopy every 2 years No barium enema
Colonoscopy every 2 years No barium enema
Medicare will pay Colonoscopy every 2 years ACBE/SCBE with restrictions
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cancer, one being a first-degree relative of another; CRC across two generations; and one cancer diagnosed in a person less than 50 years of age. The syndrome is associated with a variety of extracolonic malignancies, including carcinoma of the endometrium, ovaries, renal pelvis and ureters, stomach and small bowel. Hereditary Nonpolyposis Colorectal Cancer Amsterdam Criteria Three or more relatives with verified CRC* CRC across two generations CRC diagnosed before age 50 History of multiple, extra, colonic malignancies Clinically, patients with HNPCC develop cancers at higher frequency, an earlier age, and in a more proximal distribution than average individuals, with 65% to 85% of the tumors occurring in the proximal Given these characteristics as well as the rigorous criteria previously listed, guidelines suggest that persons with a strong family history of CRC occurring in multiple relatives and across generations should undergo examinations of the entire colon every 1 to 2 years starting between the ages of 20 to 30 and every year after age 40.9' Further recommendations include genetic testing, if possible, as well as genetic counseling. People with First Degree Relatives Who Have Had Adenomatous Polyps or CRC
Genetic syndromes of CRC represent 5% to 6% of all CRC cases at most, leaving a much larger role for familial factors in the pathogenesis of CRC. It is estimated that people with a first-degree relative with a history of CRC, especially if that relative developed cancer at an early age, have a two- to three-fold increased risk above the average population, and are more likely to develop cancer at an earlier age, so that the risk of a 40-year-old individual with a family history of CRC is equal to that of a 50-year-old average-risk person.24The distribution and progression of lesions in patients with a positive family history does not appear to be different from that in the general population; the current recommendation is to begin screening by routine methods at the age of 40 rather than at the age of 50,9' or at least 10 years before the CRC in the index case. Finally, there is evidence that a family history of adenomatous polyps adds risk for CRC in first-degree relatives particularly if the polyps occurred before age 60. These patients are commonly screened in the same manner as those with a family history of CRC. SURVEILLANCE
Surveillance, unlike screening, refers to follow-up testing (usually in the form of colonoscopy, but sometimes with DCBE) of patients with previously diagnosed colorectal disease such as polyps, CRC, or inflammatory bowel disease. Patients with Prior History of Adenom,atous Polyps
Many patients will have adenomatous polyps found and removed at the time of screening colonoscopy. The follow-up surveillance of such patients has undergone much debate over the years and only recently has there been concrete data *One relative should be first degree (parent, sibling, child)
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on which to base recommendations. It is now clear that the size of the polyp, the number of polyps, and the histologic grade is predictive of future colonic lesions. At least three studies have shown that the presence of solitary adenomas less than I-cm in size does not predict an increased likelihood of recurrent neoplastic lesion~.*,*~,8' Patients with multiple polyps, polyps with villous histologic features and those with adenomas greater than 1-cm in size require follow-up colonoscopy. Guidelines recommend repeat colonoscopy 3 years after the initial exam.91If the follow-up procedure is negative or if only one, small, tubular adenoma is found, the subsequent colonoscopy can be done in 5 years.
Surveillance of Patients with a History of CRC
Approximately one-third of patients who undergo curative-intent surgery for CRC have later recurrences, with the majority of these appearing within the initial 2 years postoperatively." Anastomotic recurrences are common, particularly after rectal or rectosigmoid resection^.^^ Some have advocated serial carcinoembryonic antigen measurements for detecting early metastatic disease, citing high positive predictive value in second-look surgical series.5sIdeally, patients should undergo a complete colonoscopic exam in the preoperative period. If this is not possible, guidelines recommend evaluation with either colonoscopy or barium enema within the first 12 months of the surgery.91If this or the preoperative study is normal, subsequent evaluation should be performed at 3 years and if normal, every 5 years thereafter.
Surveillance of Patients with Inflammatory Bowel Disease
Although fewer than 1%of all CRC cases occur in patients with inflammatory bowel disease (IBD), the relative risk and excess mortality among this population justify surveillance for CRC in these patients. Risk for CRC in the setting of inflammatory bowel disease is directly related to disease duration and anatomic extent. The risk is low in the first decade of disease but increases thereafter at a rate of approximately 0.5% to 1.0% per year.71Patients with disease proximal to the splenic flexure or with pancolitis are at greatest risk, although those with only proctitis have a risk for CRC similar to that of the average person. One study found a positive correlation between older age at initial presentation for IBD and increased risk of CRC.45Conversely, childhood onset of colitis does not appear to be associated with an increased risk independent of disease duration or anatomic extent.85Although the severity of colitis does not appear to affect risk for CRC, the discovery of dysplasia or dysplasia associated lesion or mass (DALM) on surveillance colonoscopy is predictive of concurrent or future malignancy. Results from the St. Marks Hospital surveillance study indicate that low-grade dysplasia (LGD) carries with it a substantial risk for CRC in patients with ulcerative colitis.I8At colectomy, 27% of patients with LGD had cancer already in the colon and 54% of patients with LGD developed high grade dysplasia (HGD) or CRC at 5 years. In one study, 32% to 67% of patients with HGD on colonoscopic biopsy were found to have carcinoma at the time of colectomy.8The same investigators found that only 2.5% of patients without dysplasia on initial colonoscopy eventually developed dysplasia or cancer. Risk for developing CRC in patients with Crohn's disease is a long debated topic. Although it commonly is believed that the risk is much lower in Crohn's disease than in ulcerative colitis, some investigators have shown that for similar
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anatomic extent and duration of disease, the risk in these patient populations may be equal.7s Although there are no prospective, randomized trials to support surveillance for CRC in patients with chronic inflammatory bowel disease, two retrospective studies have shown reduced mortality in patients participating in a routine surveillance program.16,19 Guidelines suggest that surveillance colonoscopy begin after 8 years of disease in those with pancolitis, or after 15 years of disease in those with colitis limited to the left colon, and that examination be repeated every 1 to 2 years.y1Since barium enema is routinely abnormal in patients with IBD, flexible sigmoidoscopy views only the left colon, and patients with inflammatory bowel disease commonly have positive FOBT, these screening methods have no role in the surveillance for CRC in patients with IBD. Typically, surveillance colonoscopy is performed with biopsy in all four quadrants of the colonic lumen at 10-cm intervals. Despite the large number of specimens taken with each exam, it is important to realize that less than 1% of the mucosa is sampled and the possibility of missing a dysplastic area is high. Consideration of total colectomy should be undertaken for patients with long standing disease and LGD and when high-grade dysplasia is revealed.
CURRENT MEDICARE POLICY
In 1997, Health and Human Services (HHS) approved CRC screening for medicare patients. Average risk (low risk) and high risk patients were defined (Table 1 and Table 2). Average risk patients have a choice between FOBT every 2 years or flexible sigmoidoscopy every 4 years. Medicare will not pay for both screening tests, nor will screening colonoscopy be reimbursed for average risk patients. Air contrast barium enema (ACBE) every 4 years can be substituted for FOBT or flexible sigmoidoscopy if the attending physician (not the radiologist) attests in writing that ACBE has an equal or greater efficacy for screening in a particular patient. Single contrast barium enema (SCBE) can be substituted if patient cannot tolerate ACBE with written attestation. All positive results require colonoscopy or surgery follow-up. High risk patients can be screened with colonoscopy every 2 years or ACBE/SCBE every 2 years with restrictions described above.
CONCLUSION
CRC is a prevalent disease with appreciable morbidity and mortality. Randomized, controlled trials have shown with reasonable certainty that screening reduces cancer deaths and is cost-effective. Despite this, surprisingly few Americans participate in routine screening programs. There are a number of factors that increase an individual's risk for CRC, including a personal or family history of adenomatous polyps or colorectal cancer, certain genetic syndromes and chronic inflammatory bowel disease. It is important for clinicians to inquire about potential risk factors and to consider these when deciding on an appropriate screening test. Patients should be informed of the various screening options available, the potential benefits of detecting CRC at an early stage, and possible complications of the individual tests. Health care providers should be sensitive to various cultural and religious factors that may influence patient acceptance and satisfaction with screening examinations. During the actual test, special attention to ensure patient modesty and avoid embarrassment
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should be made. Finally, results of screening should be conveyed in an effective and timely fashion to the primary care provider and the patient. Although there are still a number of unanswered questions and potential areas for research, screening for CRC has the potential to dramatically reduce mortality in the United States, perhaps by as much as 30,000 lives per year.” In the future, efforts should be made to increase patient understanding of the disease and the various screening methods available. As clinicians, we play a pivotal role in educating our patients, implementing screening programs, and ensuring compliance.
References 1. Allison JE, Tekawa MA, Ransom LJ, et al: A comparison of fecal occult-blood tests for
colorectal-cancer screening. N Engl J Med 334:155, 1996 2. American Cancer Society: Cancer facts and figures, 1996. Atlanta, GA, American Cancer Society, 1996 3. Anderson LM, May DS: Has the use of cervical, breast and colorectal cancer screening increased in the United States? Am J Public Health 85840, 1995 4. Atkin WS, Morson BC, Cuzik J: Long-term risk of colorectal cancer after excision of rectosigmoid adenomas. N Engl J Med 326:658, 1992 5. Barry MJ, Mulley AG, Richter JM: Effect of workup strategy on the cost-effectiveness of fecal occult-blood screening for colorectal cancer. Gastroenterology 93:301, 1987 6 . Bat L, Pines A, Ron E, et al: A community-based program of colorectal screening in an asymptomatic population: Evaluation of screening tests and compliance. Am J Gastroenterol 81:647,1986 7. Bat L, Pines A, Shemesh E, et al: Colonoscopy in patients aged 80 years or older and its contribution to the evaluation of rectal bleeding. Postgrad Med J 68:355, 1992 8. Bernstein CN, Shanahan F, Weinstein WM: Are we telling our patients the truth about surveillance colonoscopy in ulcerative colitis? Lancet 343:71, 1994 9. Bernstein MA, Feczko PJ, Halpert RD, et al: Distribution of colonic polyps: Increased incidence of proximal lesions in older patients. Radiology 15535, 1985 10. Bodmer WF, Bailey CJ, Bodmer J, et a 1 Localization of the gene for familial adenomatosis polyposis on chromosome 5. Nature 328:614, 1987 11. Boland C R Malignant tumors of the colon. In Yamada T (ed): Textbook of Gastroenterology, ed 2. Philadelphia, JB Lippincott, 1995 12. Brandeau ML, Eddy DM: The workup of asymptomatic patients with a positive fecal occult-blood test. Med Decis Making 732, 1987 13. Brown ML, Potosky AL, Thompson GB, et a 1 The knowledge and use of screening tests for colorectal and prostate cancer: Data from the 1987 National Health Survey. Prev Med 19562, 1992 14. Bussey HJR: Familial polyposis coli: Family studies, histopathology, differential diagnosis and results of treatment. Baltimore, The Johns Hopkins University Press, 1975 15. Byrd RL, Boggs HW Jr, Slagle GW, et al: Reliability of colonoscopy. Dis Colon Rectum 321023, 1989 16. Choi PM, Nugent FW,Schoetz DJ, et al: Colonoscopic surveillance reduces mortality from colorectal cancer in ulcerative colitis. Gastroenterology 105:418, 1993 17. Concept approval granted to trial of prostate, lung, colorectal and ovarian screens. Cancer Lett 15:1, 1989 18. Connell WR, Lennard-Jones JE, Williams,CB, et al: Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis. Gastroenterology 107:934,1994 19. Connell WR, Talbot IC, Harpaz N, et al: Clinicopathological characteristics of colorectal carcinoma complicating ulcerative colitis. Gut 35:1419, 1994 20. Doce R: General epidemiologic considerations in etiology of colorectal cancer. In Winawer s, Schottenfeld D and Sherlock P: Colorectal cancer: Prevention, epidemiology and screening. New York, Raven, 1980, p 3 21. Dubow RA, Katon RM, Benner KG, et al: Short (35-cm) versus long (60-cm) flexible
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42. 43. 44. 45. 46. 47.
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48. Lofti AM, Spencer RJ, Ilstrup DM, et al: Colorectal polyps and the risk of subsequent carcinoma. Mayo Clin Proc 61:337, 1986 49. Lynch HT, Krush AJ. Cancer family "G" revisited: 1895-1970. Cancer 27:1505,1971 50. Lynch HT, Smyrk T: Hereditary nonpolyposis colorectal cancer (Lynch syndrome). An updated review. Cancer 78:1149, 1996 51. Macrae FA, St John DJB, Caligore P, et al: Optimal dietary conditions for hemoccult testing. Gastroenterology 82:899, 1982 52. Macrae FA, St John DJB, Relationship between patterns of bleeding and Hemoccult sensitivity in patients with colorectal cancers or adenomas. Gastroenterology 82:891, 1982 53. Mandel JS, Bond JH, Church TR, et al: Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 328:1365,1993 54. Marshall JB, Barthel JS: The frequency of total colonoscopy and the terminal ileal intubation in the 1990s. Gastrointest Endosc 39:518, 1993 55. Martin EW, Cooperman M, Carey LC, et al: Sixty second-look procedures indicated primarily by rise in serial carcinoembryonic antigen. J Surg Res 28:389, 1980 56. M a d e WF: Screening for colorectal cancer by nurse endoscopists. N Engl J Med 330:183, 1994 57. Mayberry RM, Coates RJ, Hill HA, et al: Determinants of black/white differences in colon cancer survival. J Natl Cancer Inst 871686,1995 58. McAfee JH, Katon RM: Tiny snares prove safe and effective for removal of diminutive colorectal polyps. Gastrointest Endosc 40:301, 1994 59. McCarthy BD, Moskowitz MA: Screening flexible sigmoidoscopy: Patient attitudes and compliance. J Gen Intern Med 8:120,1993 60. McDonnell WM, Ryan JA, Seeger DM, et al: Effect of iron on the guaiac reaction. Gastroenterology 96:74, 1989 61. McKee CL, Ragland JJ, Myers JD: An evaluation of multiple clinical variables for hypoxia during colonoscopy. Surgical Gynecology and Obstetrics 173:37, 1991 62. Miller BA, Ries LA, Hankey BF Cancer statistics review: 1973-1990. Bethseda MD, National Cancer Institute; 1992. DHHS Pub1 No. (NIH) 92-2789 63. Muller AD, Sonnenburg A: Prevention of colorectal cancer by flexible endoscopy and polypectomy. A case-control study of 32,702 veterans. Ann Intern Med 123:904, 1995 64. Muller AD, Sonnenburg A: Protection by endoscopy against death from colorectal cancer. Arch Intern Med 155:1741,1995 65. Neale AV, Deiners RY, Hennan S: Compliance with colorectal cancer screening in a highrisk occupational group. J Occup Med 31:1007, 1989 66. Neilson AR and Whynes DK Determinants of persistent compliance with screening for colorectal cancer. SOCSci Med 41:365, 1995 67. Nelson RL: Iatrogenic perforation of the colon and rectum. Dis Colon Rectum 25:305, 1982 68. Newcomb PA, Norfleet RG, Storer BE, et al: Screening sigmoidoscopy and colorectal cancer mortality. J Natl Cancer Inst 84:1572, 1992 69. Ott DJ, Gelfand DW: Colorectal tumors: Pathology and detection. AJR Am J Roentgen01 131:691, 1978 70. Petersen GM, Slack J, Nakamura Y: Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage. Gastroenterology 100:1658, 1991 71. Ransohoff D F Colon cancer in ulcerative colitis. Gastroenterology 94:1089, 1988 72. Ransohoff DF and Lang CA: Screening for colorectal cancer with the fecal occult blood test: A background paper. American College of Physicians. Ann Intern Med 126:811, 1997 73. Rex DK, Lehman GA, Hawes RH, et al: Screening colonoscopy in asymptomatic averagerisk persons with negative fecal occult blood tests. Gastroenterology'100:64, 1991 74. Rich T, Gunderson LL, Lew R, et al: Patterns of recurrence of rectal cancer after potentially curative surgery. Cancer 52:1317, 1983 75. Sachar DB: Cancer in Crohn's disease: Dispelling the myths. Gut 35:1507,1994 76. Selby JV, Friedman GD: Sigmoidoscopy in the periodic health examination of asymptomatic adults. JAMA 261:594, 1989 77. Selby JV, Friedman GD, Collen MF: Sigmoidoscopy and mortality from colorectal cancer: The Kaiser Permanente Multiphasic Evaluation Study. J Clin Epidemiol41:427, 1988
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78. Selby JV, Friedman GD, Quesenberry CP Jr, et al: A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 326653, 1992 79. Selby JV, Friedman GD, Quesenberry CP Jr, et a 1 Effect of fecal occult blood testing on mortality from colorectal cancer. A case-control study. Ann Int Med 118:1, 1993 80. Shapiro M: Colorectal cancer screening by paramedical personnel. Dig Dis Sci 29:159, 1984 81. Spencer RJ, Melton LJ 111, Ready RL, et al: Treatment of small colorectal polyps: A study of the risk of subsequent carcinoma. Mayo Clin Proc 59:305, 1984 82. St John DJB, Young GP, Alexeyeff MA, et al: Evaluation of new occult blood tests for detection of colorectal neoplasia. Gastroenterology 1041661, 1993 83. Steinberg SM,Barkin JS, Kaplan RS, et al: Prognostic indicators of colon tumors: The gastrointestinal tumor study experience. Cancer 571866, 1986 84. Stroehlein JR, Fairbanks VF, Go VLW, et al: Hemoccult stool tests-false-negative results due to storage of specimens. Mayo Clin Proc 51:548,1976 85. Sugita A,Sachar DB, Bodian C, et al: Colorectal cancer in ulcerative colitis: Influence of anatomical extent and age at onset on colitis-cancer interval. Gut 32:167, 1991 86. Tripp MR, Morgan TR, Sampliner RE, et a1 Synchronous neoplasms in patients with diminutive colorectal adenomas. Cancer 60:1599, 1987 87. Wagner JL, Tunis S, Brown M, et al: Cost-effectiveness of colorectal cancer screening in average-risk adults. ln Young G and Levin B (eds): Prevention and early detection of colorectal cancer. London, WB Saunders, 1996 88. Waye JD, Lewis BS, Frankel A, et al: Small colon polyps. Am J Gastroenterol118:63,1988 89. Waye JD, Lewis BS, Yessayan S: Colonoscopy: A prospective report of complications. J Clin Gastroenterol 15:347, 1992 90. Winawer SJ, Flehinger BJ, Schottenfeld D, et al: Screening for colorectal cancer with fecal occult blood testing and sigmoidoscopy. J Natl Cancer Inst 85:1311,1993 91. Winawer SJ, Fletcher RH, Miller L, et a1 Colorectal cancer screening: Clinical guidelines and rationale. Gastroenterology 112594, 1997 92. Winawer SJ, Miller C, Lightdale CI, et al: Patient response to sigmoidoscopy: A randomized controlled trial of rigid and flexible sigmoidoscopy. Cancer 601905, 1987 93. Wingo PA, Tong T, Bolden S Cancer Statistics 1995. Cancer 45:8,1995
Address reprint ~equestst o Timothy T. Nostrant, MD University of Michigan 3912 Taubman Center Ann Arbor, MI 48109-0362 email: dmharris8medmail.med.umich.edu
ONCOLOGY
+ .OO
SCREENING FOR COLORECTAL CANCER Michelle A. Jediiak, MD and Timothy T. Nostrant, MD
The last decade has seen an exponential rise in our understanding of the epidemiology, cause and natural course of colorectal cancer (CRC). A number of randomized, controlled studies evaluating cancer screening methods have recently been completed and published. Results of these studies have enabled clinicians to make educated decisions and recommendations when counseling their patients as to the various screening modes available and in choosing optimal screening programs. This article will review the most current information on CRC including epidemiology, clinical features, available screening methods and their respective values, and will offer recommendations on effective implementation in clinical practice.
EPIDEMIOLOGY
CRC is the second leading cause of cancer death, representing approximately 14% of all cancer-related mortality, and the third most frequently diagnosed malignancy in the United States, following only lung and prostate cancer.*Risk factors for CRC include advanced age, several life-style factors, personal or family history of colorectal adenoinatous polyps or cancer, and inflammatory bowel disease, as well as several hereditary syndromes such as Lynch syndrome and familial adenomatous polyposis (FAP). CRC Risk Factors Age > 50 High fat/low calcium diets Low vegetable intake Obesity Smoking Personal/family history of polyps/CRC From the Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, Michigan PRIMARY CARE VOLUME 25 .NUMBER 2 IUNE 1998 9
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Inflammatory bowel disease (CUC, Crohn's, colitis) Hereditary syndromes Familial adenomatous polyposis (FAP) Hereditary nonpolyposis colon cancer Isolated colon cancer (Lynch 1) Multiple cancers Uterine Ovarian Breast Colon Gastric Pancreatic Thyroid Lung There is wide geographic variation in CRC incidence, with industrialized nations being at greater risk than developing countries.*"Interestingly, these differences do not appear to be solely genetically determined since migration from a low- to high-risk area is associated with increased rates of CRC.3nThis finding supports an environmental or dietary role in the causation of CRC. CRC occurs with slightly higher frequency in African-Americans than in whites, with higher mortality in native Alaskans6'; incidence in men and women is approximately Finally there is evidence that the regular use of nonsteroidal anti-inflammatory drugs may decrease risk for colorectal adenomas as well as cancer. Giardiello et a1 found that sulindac given twice daily for 9 months decreased both the size and number of colorectal polyps in patients with familial adenomatous polyposis.26Similarly, a prospective cohort study by Giovannucci et a1 showed that patients using two or more aspirin per week had a 32% reduction in risk for colorectal cancer and a 28% reduction in risk for colorectal adenomas compared with nonusers.27
CLINICAL MANIFESTATIONS
Colorectal cancer may present in a variety of ways and depends to some degree on the size and location of the tumor. Cancers of the proximal colon can grow large and often bleed for a prolonged period prior to detection, resulting in iron deficiency, anemia, and sometimes hematochezia. Local invasion of adjacent organs can result in pain or may produce symptoms specific to the organ that it invades. For example, invasion of the bladder may cause pneumaturia. Occasionally, tumor growth through the muscularis propria will result in perforation and the patient will present with an acute abdomen. Since the lumen of the transverse, descending, and sigmoid colons are narrow relative to the cecum and ascending colon, these are common sites for obstructing tumors. Patients with obstruction may present with abdominal distention, pain, nausea, vomiting, change in bowel habits or in stool diameter (e.g., pencil stools). Obstruction as a presenting sign suggests the presence of a large tumor, and is associated with significantly reduced survival.83Finally, patients may present with nonspecific symptoms such as anorexia or weight loss. Often colorectal tumors do not prbduce symptoms until late in the natural course of the disease. Therefore, a majority of patients whose first evaluation is at the time of clinical symptoms will have advanced cancer and likely will die of their disease. This is supported by the findings of Hardcastle et a1 who prospectively evaluated patients for CRC with and without screening fecal occult blood testing (FOBT). This study followed more than 150,000 patients over a mean in-
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terval of 7.8 years and found that individuals who did not undergo evaluation until the time of symptom presentation were significantly more likely to have advanced stage tumors (Dukes' C or D) and die from colorectal cancer than screened individual^.^^ It is crucial, therefore, that screening strategies be designed to detect disease prior to clinical manifestations and at earlier, treatable stages. RATIONALE FOR SCREENING
Currently, many Americans are not screened for CRC; information from the National Health Interview Survey indicates that only 17%of people over 50-yearsold underwent fecal occult blood testing (FOBT) in 1991 and only 9.4%underwent sigmoidoscopy in the prior three year^.^,'^ Uncertainty about screening methods, frequency of testing, populations to be screened and the cost-effectiveness of various testing methods has precluded agreement among health care professionals as to screening for this prevalent and potentially treatable disease. In 1994, the Federal Agency for Health Care Policy and Research (AHCPR) joined with the American Gastroenterology Association (AGA) in a combined effort to critically review the evidence on CRC and to develop guidelines based on their findings. These guidelines were based on information from 350 key articles selected from a MEDLINE search of the scientific literature and were published in a detailed article in the February 1997 issue of Gastroenter~logy.~' Screening refers to tests that identify persons at-risk for a particular disease, but without symptoms, signs or easily identifiable risk factors. Screening is deemed effective and valuable when a number of conditions are met. The disease must be common and associated with significant morbidity or mortality. CRC is quite common, with an estimated lifetime risk of 6% in asymptomatic, average risk individuals. Available screening tests must have adequate sensitivity in detecting early stage disease, must be acceptable to patients and must be available in clinical practice, The various screening tests for CRC that are currently available have sensitivities ranging from 40% to 90%.Further, few polyps advance to cancer (approximately2.5 per 1000 polyps per year),Z3and the progression from adenomatous polyp to carcinoma occurs slowly over many years, although the precise time interval for transformation is unknown. Diagnosis and treatment at an earlier disease stage must provide improved outcome over detection through clinical presentation at a later disease stage. In the case of CRC, it is well established that advanced tumor stage is associated with decreased survival (33%for Dukes' Stage C at 5 years versus 64% to 85% for Dukes' Stage A or B at 5 years).93Multiple controlled trials have established with reasonable certainty that detecting early-stage CRC is possible with appropriate screening method^.^^,^^,^^,^^,^^,^^ Finally, the screening test should be cost-effective and have acceptably low risk when compared to potential benefit. Several cost-effectiveness analyses have shown that FOBT, flexible sigmoidoscopy, double contrast barium enema and colonoscopy can cost less than $20,000 per year of quality life saved, a figure comparable or better than that for other commonly screened-for cancers such as breast or cervical It is estimated that the cost per person (entered at 50-yea:s-oldf will range from $250 to $1200 depending on screening interval, method used, and billing costs for a particular procedure in a given geographic area.22,46 CRC SCREENING IN PERSONS AT AVERAGE RISK
Persons over the age of 50 without a history of inflammatory bowel disease or genetic syndromes associated with CRC, and without a personal or family
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history of CRC or adenomatous polyps, are defined as those at average risk of developing CRC. Individuals with symptoms suggestive of polyps or colorectal cancer or with a history of gastrointestinal bleeding are not candidates for screening and should be offered appropriate diagnostic examinations. Based on a critical review of the available literature, a multidisciplinary panel representing the AGA with the endorsement of the American Cancer Society, the American College of Gastroenterology, the American Society of Colon and Rectal Surgeons and others, have recommended that screening in average-risk individuals begin at the age of 50 and use either FOBT, flexible sigmoidoscopy, a combination of FOBT and sigmoidoscopy, double contrast barium enema (DCBE), or colono~copy.~~ (Table 1)
Fecal Occult Blood Testing Stool guaiac tests test for peroxidase activity using a colorless indicator, guaiac gum, that is oxidized to a pigmented quinone in the presence of peroxidase and hydrogen peroxide. Hemoglobin has pseudoperoxidase activity, therefore bleeding polyps or cancers within the colon will give a positive reaction. Sensitivity of guaiac-based tests are closely related to the amount of blood in the stool. Stool hemoglobin concentrations less than 2 mL/g of stool usually result in a negative Blood loss must be in the range of 10 mL per day to produce a consistently positive result on FOBT. Additional factors may influence the sensitivity and specificity of the test, including rare red meats, turnips, horseradish (false positive), Vitamin C (false negative), and salicylates (false p~sitive).~’ There has been considerable debate as to the effect of oral iron on stool guaiac tests. Although oral iron probably does not cause false positive reactions or induce GI a study by McDonnell et a1 reported that the black pigment in stools of patients on iron supplements could be misinterpreted as positive.60Further, the length of storage may affect test sensitivity; one study showed decreased reaction intensity after 4 days and false negative reactions in 8 days.R4Rehydration improves sensitivity of testing at the cost of increased false positives.s1 When administered to asymptomatic populations, FOBTs are positive approximately 1%to 16% of the time?’ with reported sensitivities for cancer ranging from 38% to 96% depending on the test used as well as the size and location of t ~ m ~ r .Reported ~ ~ J ~specificities , ~ ~ range from 88% to 98%. A study by Allison et
Table 1. COLORECTAL CANCER SCREENING RECOMMENDATIONS Average-Risk Patient Onset of Screening Age
2
50
Screening Tests Fecal Occult Blood Test (FOBT) Flexible sigmoidoscopy (FS) FOBT/FS combination Air contrast barium enema Colonoscopy
Frequency Yearly Every 5 years
Other Recommendations Medicare will pay FOBT every year FS every 4 years
FS or FOBT (not both) Every 5-1 0 years Every 10 years
Air contrast barium enema with restrictions* Not colonoscopy
’Attending must attest in writing that ACBE is equal to or greater than FOBT or FS in a particular patient Single contrast BE can be ordered at attending discretion
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a1 compared the performance characteristics of three FOBTs (Hemoccult 11, Hemoccult I1 Sensa and Hemeselect) and found Hemoccult I1 Sensa had the highest sensitivity for carcinomas (79.4%)while Hemoccult I1 had the highest specificity (97.7%).' Overall, Hemeselect and a combination test in which Hemeselect was used to confirm positive Hemoccult I1 Sensa results provided the greatest positive predictive value in detecting colorectal carcinomas and polyps. When the colons of persons with positive test results are evaluated, colorectal cancers are found in 2% to 17% of patients7' To date, three randomized controlled studies, one case-control study and one nonrandomized controlled study have demonstrated a reduction in death from colorectal cancer in patients screened with FOBTs followed by colonoscopy in guaiac-positive i n d i v i d ~ a l s . ~ Strong, ~ ~ ~ ~ ~direct ~ ~ , ~evidence ~ , ~ " for the effectiveness of FOBT has prompted recommendations for annual screening over biannual screening based on results from the Minnesota Colon Cancer Control which showed a 33% reduction in mortality in annually screened patients and no significant reduction in mortality in patients screened every 2 years. Persons with a positive FOBT should undergo evaluation of the entire colon and rectum either with'colonoscopy or with double contrast barium enema, preferably coupled with flexible sigmoidoscopy. Compliance with FOBT varies widely between regions, patient populations and practitioners. Characteristics associated with increased compliance include female sex: higher socio-economic status2 more personal and family experiences with illness>b regular visits to a dentistbhand membership in a health maintenance organization (HMO).I3The role of the clinician in achieving compliance with a screening regimen is also significant.hsVarious compliance factors, coupled with the relatively modest reduction in mortality offered by FOBT in comparison with alternate means of screening, must be considered by the health care provider when choosing this as the standard screening technique for his or her practice.
Sigmoidoscopy
The standard sigmoidoscope employed in clinical practice is a flexible scope, 35-cm or-60 cm in length. Under optimal conditions, the 35-cm scope is able to reach only the proximal sigmoid colon, although the 60-cm scope routinely reaches the descending colon sometimes to the level of the splenic flexure and beyond. Prior to testing, the bowel is prepared using saline enemas or an oral cathartic solution. Patients generally are not sedated for the procedure because most patients experience only mild to moderate discomfort during the exam.21,92 The procedure typically lasts 10m to 15m, but performance time may vary depending on the skill and experience of the e n d o ~ c o p i s and t ~ ~the ~ ~adequacy ~~~ of the bowel preparation. Sigmoidoscopy offers important advantages over FOBT for CRC screening. It allows direct visualization of the bowel wall as well as the capacity to biopsy or remove suspicious lesions. The most serious potential complication of sigmoidoscopy is perforation of the colon, although this is rare, with rates ranging from one to three cases in 10,000 examinatioi~s.~~ Other rare complications include iatrogenic infection and bleeding postbiopsy. Sigmoidoscopic exams reaching the proximal end of the sigmoid colon have been shown to detect approximately 50% of colonic polyps and cancer^^^,^^ with approximately one-third to one-half occurring proximal to the area visualized in a standard p r o c e d ~ r e . ~Several , ~ ~ , ~case ~ , ~control ~ ~ t ~ d i have e ~ demonstrated ~ ~ , ~ ~ , ~ ~ a decrease in cancer related mortality in patients undergoing sigmoidoscopic screening, primarily with rigid sigmoidoscopy. Although a randomized controlled
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trial of flexible sigmoidoscopy for the prevention of CRC is currently in progress,” no such study has been published yet. Given that few polyps arise and progress to advanced cancer in less than 5 years and the findings from one study showing a protective effect against death from CRC by endoscopy of at least 6 current recommendations offer screening sigmoidoscopy at 5 year i n t e r v a l ~ Persons .~~ with polyps greater than I-cm in diameter and those with cancer on flexible sigmoidoscopy should undergo full colonoscopic examinations. Controversy exists over the work-up of patients with adenomatous polyps less than I-cm in diameter, but evidence suggests that approximately one-third of these patients will have additional adenomatous polyps in the proximal colon and an equal number of patients will have polyps in the proximal colon while having no polyps or nonneoplastic polyps in the distal colon,’736 No specific recommendations with regard to this population are made in the recently published AGA guideline^.^^ Factors that influence compliance with screening sigmoidoscopy are similar to those noted for FOBT and include female gender, higher income, routine health evaluations, older age and a family history of c a n ~ e r . ’ ~ , ~ ~ Combined FOBT and Sigmoidoscopy
Current guidelines support combined annual FOBT and sigmoidoscopy at 5 year intervals as an acceptable method of CRC screening, noting that sigmoidoscopy complements FOBT through increased sensitivity for detecting adenomatous polyps and cancers of the left Further, sigmoidoscopy provides an opportunity for identifying adenomatous polyps and for potentially reducing CRC, or at least detecting it an earlier stage. This recommendation is supported by a large, nonrandomized, controlled study in which patients were assigned to either FOBT with rigid sigmoidoscopy or rigid sigmoidoscopy alone.9oPatients in the combined screening group had an approximately 55% reduction in CRC mortality compared with the group receiving sigmoidoscopy alone. Barium Enema
Prior to undergoing barium enema, the bowel is prepared using a prescribed low-residue or liquid diet, usually taken on the day prior to the procedure, as well as laxatives or cathartic solutions on the evening prior to the test. Radiologic examination of the colon can be performed using either a single- or double-contrast technique. In single contrast studies, the entire colon is a filled with a liquid lowdensity barium suspension via a small tube inserted into the rectum approximately 3-cm to 4-cm. The examination is performed with palpation and various compression maneuvers under fluoroscopic monitoring. Radiographic images are obtained when barium reaches the cecum. In double contrast studies, a smaller volume of high density barium is instilled into the colon followed by insufflation of air. Although more difficult to perform and physician-intensive, double contrast barium enema (DCBE) is superior to single contrast studies in demonstrating fine mucosal lesions such as polyps and nonobstructing cancers.69Complications in barium enemas are rare; perforation, the most serious complication, occurs at a rate of 1 per 25,000 cases. Reported sensitivities of DCBE for colorectal cancer range from 70% to 95%; however, there exists an irreducible minimum error rate of approximately 5%40 that is largely caused by interpretation and suboptimal studies even in very experienced hands. Though insertion of barium is simple, instilling the correct quan-
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tities of the barium and air and providing appropriate compression requires time and skill on the part of a dedicated radiologist. If a high quality study is obtained, there can be difficulties in interpretation that are caused by patient anatomy or muscle spasm, and false positive readings caused by adherent stool or air bubbles. In addition, patients with an abnormality on DCBE likely will require colonoscopy, although very few colonoscopic findings require further evaluation with DCBE. Therefore, pretest probability of disease is very important in choosing between DCBE and colonoscopy. This is because colonoscopy, unlike DCBE, allows biopsy or snare excisions of lesions and DCBE does not. Nonetheless, DCBE is a safe, simple procedure with satisfactory patient acceptance and retains a useful role in CRC screening. With regard to cost-effectiveness, a recent review by Gelfandz5concluded that barium enema was the most cost-effective method of CRC screening, although others have found colonoscopy and barium enema to have comparable cost-effectiveness5~1z with actual cost varying according to procedure charges, work-up algorithms and frequency of screening employed. Some have recommended combined flexible sigmoidoscopy and DCBE as a screening technique, citing the added sensitivity of flexible sigmoidoscopy for lesions in the rectosigmoid C O ~ O ~ . * ~ Currently, there are no studies assessing optimal screening intervals of DCBE for CRC. Guidelines recommend DCBE, preferably with flexible sigmoidoscopy, every 5 to 10 years." Colonoscopy
Preparation for colonoscopy sometimes can begin days prior to the procedure with modifications in diet and medications. Patients with chronic constipation or those with a history of inadequate prep on previous exams often are placed on a liquid diet a day or two prior to the test. Persons on oral iron therapy are advised to stop the medication 4 to 5 days prior to colonoscopy, since iron may combine with vegetable residue changing the mucosal appearance of the colon and producing a sticky film that is difficult to clear. Aspirin, warfarin and other antiplatelet or anticoagulant drugs are held for 7 days prior to the test in order to reduce the risk of immediate or delayed bleeding in cases for which polypectomy is performed. One of any number of osmotic or isotonic cathartic solutions is administered to cleanse the bowel the evening prior to the examination. Even patients with a history of diarrhea or defunctionalized bowel will require some degree of preparation as stool residue in these patients can significantly obscure mucosal evaluation, though larger lesions are seldom missed. Generally, patients receive intravenous sedation at the time of colonoscopy, which provides pain control and amnestic benefits. In most centers, patients are monitored for cardiorespiratory complications throughout the procedure. The colonoscopic exam is performed using a high resolution flexible endoscope 15mm to 17mm in diameter and 165cm in length. The scope is introduced through the anus and advanced to the cecum while the endoscopist views tip progression via a full color video monitor. The procedure typically takes 20 to 30 minutes, but duration may vary with the skill of the examiner, patient anatomy, and ade-quacy of bowel preparation. Unlike any of the other screening methods previously reviewed, colonoscopy offers the ability to view the entire colon and to biopsy or remove any suspicious lesions through electrocautery with forceps or a wire snare. Colonic intubation to the cecum is achieved in over 90% of cases.54Incomplete exams should be followed with either barium enema or repeat colonoscopy. Although the accuracy of colonoscopy in detecting lesions greater than l-cm in size is 90% to 95%, it is estimated that smaller lesions are missed 10% to 25% of the
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time.'s,35,36,sn This is partly caused by blind spots including acute bends and flexures as well as poor preparation and redundant or mobile colons. Colonoscopy can produce vagally-mediated dysrhythmias, hypotension and hypoxia and is therefore contraindicated for weeks to months following myocardial infarction.6' Respiratory depression can occur secondary to sedation and many patients experience abdominal pain or discomfort caused by air insufflation during or after the examination. More serious complications include perforation (-1/1,000 exams), major hemorrhage (-3/1000 exams) and death (1 to 3/10,000 exams).28,3Y,39,5h,73,89 A study by Bat and colleagues7concluded that older patients are no more likely to experience complications than younger patients. Indirect evidence has shown that colonoscopy as a screening method for CRC reduces mortality, and a case-control study by Muller et a1 demonstrated that patients undergoing colonoscopy had a 39% reduction in CRC events over controls."3Current guidelines recommend screening colonoscopy be performed at 10year intervals." Though there are no studies that specifically address frequency of screening colonoscopy, this interval was chosen on the basis that the natural history of polyp growth in familial polyposis required ten years for the development of advanced lesions. In addition, sigmoidoscopy afforded protection from distal CRC for 10 years in case-controlled
CRC SCREENING IN PERSONS AT INCREASED RISK A number of factors can put an individual at risk for CRC; screening recommendations for these individuals are outlined in Table 2. Genetic Syndromes
Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disorder with an 80% to 100% penetrance"' resulting from a mutation in the APC gene on the long arm of chromosome 5.1° Actual mutations vary among affected kindreds, but the majority code for a truncated, inactive protein. The APC protein functions to regulate cell growth and therefore has a tumor suppressor role with mutation resulting in deregulation and occurrence of CRC at an early age. It is estimated that patients who inherit the mutated gene have a 50% chance of developing CRC by 16-years-of-age70and a nearly 100% risk of developing CRC by young adulthood. Men and women are affected equally and polyps are evenly distributed throughout the Variants of familial polyposis have been described with few polyps and late onset CRC. Once polyp formation has occurred, surveillance colonoscopy is no longer useful because of the multitude of polyps (averaging >lo00 in patients with fully expressed FAP) and consideration of total colectomy should be undertaken. Genetic testing by linkage analysis can be performed if blood from affected family members is available. In patients who are known gene carriers or are indeterminate carriers, flexible sigmoidoscopy to assess for gene expression should be initiated at puberty and performed annually thereafter. Detection of polyps should prompt referral for colectomy. Hereditary nonpolyposis colorectal cancer (HNPCC), commonly referred to as Lynch syndrome, is also an inherited autosomal dominant disease caused by mutations in DNA mismatch repair genes.s0The HNPCC gene displays high penetrance but age of presentation is variable. The diagnosis is primarily clinical with criteria (referred to as the Amsterdam criteria) developed by an international collaboration and is as follows: Three or more relatives with a verified colorectal
.
*Attending must attest in writing that ACBE is equal/greater than FOBT or Single contrast BE can be ordered at attending discretion. "Any first degree relative: parent, sibling, child. Multiple second/third degree relatives tGenetic testing has limitations Expert counseling crucial Sulindac (Glindoril) may be helpful in particular situations --Delay surgery (FAP, Gardner's) -Poor operative risk (FAP, Gardner's)
Gardner's syndrome
Familial adenomatous polyposis (FAP)
index case 10 years earlier than index case (usually adolescence) Same as FAP
10 years earlier than
After 7 years disease
Chronic ulcerative colitis
Hereditary colon cancer syndrome Hereditary nonpdyposis CRC (HNPCC)
After 7 years disease
Inflammatory Bowel Disease Crohn's colitis
FS in a particular patient
Colonoscopy
Colonoscopy
Colonoscopy
Colonoscopy
Colonoscopy
Colonoscopy
10 years earlier than
PersonaVFamily Hx polyps/CRC** index case
Screening Tests
Onset of Screening
Hight-Risk Patient
Table 2. COLORECTAL CANCER SCREENING RECOMMENDATIONS
Yearlyt
Every 1 to 2 years Yearly after age 40t Yearlyt
Yearly (>20 years of disease)
Every 1 to 2 years (<20 years of disease)
Every 3 to 5 years
Frequency
Other Recommendations
-
Colonoscopy every 2 years No barium enema
Colonoscopy every 2 years No barium enema
Medicare will pay Colonoscopy every 2 years ACBE/SCBE with restrictions
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cancer, one being a first-degree relative of another; CRC across two generations; and one cancer diagnosed in a person less than 50 years of age. The syndrome is associated with a variety of extracolonic malignancies, including carcinoma of the endometrium, ovaries, renal pelvis and ureters, stomach and small bowel. Hereditary Nonpolyposis Colorectal Cancer Amsterdam Criteria Three or more relatives with verified CRC* CRC across two generations CRC diagnosed before age 50 History of multiple, extra, colonic malignancies Clinically, patients with HNPCC develop cancers at higher frequency, an earlier age, and in a more proximal distribution than average individuals, with 65% to 85% of the tumors occurring in the proximal Given these characteristics as well as the rigorous criteria previously listed, guidelines suggest that persons with a strong family history of CRC occurring in multiple relatives and across generations should undergo examinations of the entire colon every 1 to 2 years starting between the ages of 20 to 30 and every year after age 40.9' Further recommendations include genetic testing, if possible, as well as genetic counseling. People with First Degree Relatives Who Have Had Adenomatous Polyps or CRC
Genetic syndromes of CRC represent 5% to 6% of all CRC cases at most, leaving a much larger role for familial factors in the pathogenesis of CRC. It is estimated that people with a first-degree relative with a history of CRC, especially if that relative developed cancer at an early age, have a two- to three-fold increased risk above the average population, and are more likely to develop cancer at an earlier age, so that the risk of a 40-year-old individual with a family history of CRC is equal to that of a 50-year-old average-risk person.24The distribution and progression of lesions in patients with a positive family history does not appear to be different from that in the general population; the current recommendation is to begin screening by routine methods at the age of 40 rather than at the age of 50,9' or at least 10 years before the CRC in the index case. Finally, there is evidence that a family history of adenomatous polyps adds risk for CRC in first-degree relatives particularly if the polyps occurred before age 60. These patients are commonly screened in the same manner as those with a family history of CRC. SURVEILLANCE
Surveillance, unlike screening, refers to follow-up testing (usually in the form of colonoscopy, but sometimes with DCBE) of patients with previously diagnosed colorectal disease such as polyps, CRC, or inflammatory bowel disease. Patients with Prior History of Adenom,atous Polyps
Many patients will have adenomatous polyps found and removed at the time of screening colonoscopy. The follow-up surveillance of such patients has undergone much debate over the years and only recently has there been concrete data *One relative should be first degree (parent, sibling, child)
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on which to base recommendations. It is now clear that the size of the polyp, the number of polyps, and the histologic grade is predictive of future colonic lesions. At least three studies have shown that the presence of solitary adenomas less than I-cm in size does not predict an increased likelihood of recurrent neoplastic lesion~.*,*~,8' Patients with multiple polyps, polyps with villous histologic features and those with adenomas greater than 1-cm in size require follow-up colonoscopy. Guidelines recommend repeat colonoscopy 3 years after the initial exam.91If the follow-up procedure is negative or if only one, small, tubular adenoma is found, the subsequent colonoscopy can be done in 5 years.
Surveillance of Patients with a History of CRC
Approximately one-third of patients who undergo curative-intent surgery for CRC have later recurrences, with the majority of these appearing within the initial 2 years postoperatively." Anastomotic recurrences are common, particularly after rectal or rectosigmoid resection^.^^ Some have advocated serial carcinoembryonic antigen measurements for detecting early metastatic disease, citing high positive predictive value in second-look surgical series.5sIdeally, patients should undergo a complete colonoscopic exam in the preoperative period. If this is not possible, guidelines recommend evaluation with either colonoscopy or barium enema within the first 12 months of the surgery.91If this or the preoperative study is normal, subsequent evaluation should be performed at 3 years and if normal, every 5 years thereafter.
Surveillance of Patients with Inflammatory Bowel Disease
Although fewer than 1%of all CRC cases occur in patients with inflammatory bowel disease (IBD), the relative risk and excess mortality among this population justify surveillance for CRC in these patients. Risk for CRC in the setting of inflammatory bowel disease is directly related to disease duration and anatomic extent. The risk is low in the first decade of disease but increases thereafter at a rate of approximately 0.5% to 1.0% per year.71Patients with disease proximal to the splenic flexure or with pancolitis are at greatest risk, although those with only proctitis have a risk for CRC similar to that of the average person. One study found a positive correlation between older age at initial presentation for IBD and increased risk of CRC.45Conversely, childhood onset of colitis does not appear to be associated with an increased risk independent of disease duration or anatomic extent.85Although the severity of colitis does not appear to affect risk for CRC, the discovery of dysplasia or dysplasia associated lesion or mass (DALM) on surveillance colonoscopy is predictive of concurrent or future malignancy. Results from the St. Marks Hospital surveillance study indicate that low-grade dysplasia (LGD) carries with it a substantial risk for CRC in patients with ulcerative colitis.I8At colectomy, 27% of patients with LGD had cancer already in the colon and 54% of patients with LGD developed high grade dysplasia (HGD) or CRC at 5 years. In one study, 32% to 67% of patients with HGD on colonoscopic biopsy were found to have carcinoma at the time of colectomy.8The same investigators found that only 2.5% of patients without dysplasia on initial colonoscopy eventually developed dysplasia or cancer. Risk for developing CRC in patients with Crohn's disease is a long debated topic. Although it commonly is believed that the risk is much lower in Crohn's disease than in ulcerative colitis, some investigators have shown that for similar
304
IEDNAK 8z NOSTRANT
anatomic extent and duration of disease, the risk in these patient populations may be equal.7s Although there are no prospective, randomized trials to support surveillance for CRC in patients with chronic inflammatory bowel disease, two retrospective studies have shown reduced mortality in patients participating in a routine surveillance program.16,19 Guidelines suggest that surveillance colonoscopy begin after 8 years of disease in those with pancolitis, or after 15 years of disease in those with colitis limited to the left colon, and that examination be repeated every 1 to 2 years.y1Since barium enema is routinely abnormal in patients with IBD, flexible sigmoidoscopy views only the left colon, and patients with inflammatory bowel disease commonly have positive FOBT, these screening methods have no role in the surveillance for CRC in patients with IBD. Typically, surveillance colonoscopy is performed with biopsy in all four quadrants of the colonic lumen at 10-cm intervals. Despite the large number of specimens taken with each exam, it is important to realize that less than 1% of the mucosa is sampled and the possibility of missing a dysplastic area is high. Consideration of total colectomy should be undertaken for patients with long standing disease and LGD and when high-grade dysplasia is revealed.
CURRENT MEDICARE POLICY
In 1997, Health and Human Services (HHS) approved CRC screening for medicare patients. Average risk (low risk) and high risk patients were defined (Table 1 and Table 2). Average risk patients have a choice between FOBT every 2 years or flexible sigmoidoscopy every 4 years. Medicare will not pay for both screening tests, nor will screening colonoscopy be reimbursed for average risk patients. Air contrast barium enema (ACBE) every 4 years can be substituted for FOBT or flexible sigmoidoscopy if the attending physician (not the radiologist) attests in writing that ACBE has an equal or greater efficacy for screening in a particular patient. Single contrast barium enema (SCBE) can be substituted if patient cannot tolerate ACBE with written attestation. All positive results require colonoscopy or surgery follow-up. High risk patients can be screened with colonoscopy every 2 years or ACBE/SCBE every 2 years with restrictions described above.
CONCLUSION
CRC is a prevalent disease with appreciable morbidity and mortality. Randomized, controlled trials have shown with reasonable certainty that screening reduces cancer deaths and is cost-effective. Despite this, surprisingly few Americans participate in routine screening programs. There are a number of factors that increase an individual's risk for CRC, including a personal or family history of adenomatous polyps or colorectal cancer, certain genetic syndromes and chronic inflammatory bowel disease. It is important for clinicians to inquire about potential risk factors and to consider these when deciding on an appropriate screening test. Patients should be informed of the various screening options available, the potential benefits of detecting CRC at an early stage, and possible complications of the individual tests. Health care providers should be sensitive to various cultural and religious factors that may influence patient acceptance and satisfaction with screening examinations. During the actual test, special attention to ensure patient modesty and avoid embarrassment
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should be made. Finally, results of screening should be conveyed in an effective and timely fashion to the primary care provider and the patient. Although there are still a number of unanswered questions and potential areas for research, screening for CRC has the potential to dramatically reduce mortality in the United States, perhaps by as much as 30,000 lives per year.” In the future, efforts should be made to increase patient understanding of the disease and the various screening methods available. As clinicians, we play a pivotal role in educating our patients, implementing screening programs, and ensuring compliance.
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Address reprint ~equestst o Timothy T. Nostrant, MD University of Michigan 3912 Taubman Center Ann Arbor, MI 48109-0362 email: dmharris8medmail.med.umich.edu