20 Colorectal Cancer: Screening, Surveillance, and Follow-Up
Abstract
Despite the plethora of publications on the subject of follow-up strategies for patients who have undergone curative resection for colorectal carcinoma, there is no general agreement on the optimal follow-up program. The efficacy of aggressive and intensive surveillance remains a topic of intense debate. Some data support the contention that surveillance leads to increased rates of early detection and resection of recurrence, but this has not necessarily always translated into improved survival. What constitutes the ideal or even preferred follow-up program remains controversial, and this is clearly reflected by the lack of uniformity among practicing clinicians.
It is important that patients understand the limitations of the postoperative follow-up no matter how minimal or extensive it is. They should actively participate in the decision-making of the follow-up plan. Guidelines from some major societies are helpful on this issue.
20.1 Screening
Screening, which refers primarily to a population approach, has been used interchangeably with early detection. Case finding refers to early detection on an individual basis. These terms refer to the identification of individuals with an increased probability of having colorectal neoplasia. Effective screening tests meet certain criteria. The test should have scientific evidence of effectiveness and identify a significant disease. The benefits should outweigh the harm, and the screened disease should be preventable or treatable when identified. Screening for colorectal cancer meets these criteria.
20.2 Colorectal Carcinoma
In 2018, there were 140,250 estimated new cases of colon and rectal carcinomas in the United States, and of these, 40,500 (29%) were carcinomas of the rectum. 1 Of these, 50,630 (combined colon and rectum) will die, a death rate of 36%. 1 Survival for colon and rectal carcinoma is closely related to the clinical and pathologic stage of the disease at diagnosis. Data from the German Multicenter Study in colorectal carcinoma showed 5-year survival rates in stages I, II, III, and IV as 76, 65, 42, and 16%, respectively (surgical mortality not excluded). 2 More recent National Cancer Institute SEER Cancer Statistics Review for 1975–2013 demonstrated a 5-year survival of 90.1% for localized disease, 71.2% for regional, and 13.5% for distal metastatic disease. 3
It has become clear that if the disease can be detected at an early stage, the overall prognosis can be improved, with another benefit that some colorectal carcinomas can even be prevented. Most colorectal carcinomas are asymptomatic until a late stage, when some partial obstruction occurs, causing abdominal pain or change in bowel habits. Although carcinoma of the colon and rectum bleeds occasionally and unpredictably, it may be possible to diagnose it in an early stage by examining for occult blood in the stool. Through many observations and studies, including current knowledge of molecular genetics of colorectal carcinoma, the natural history of colorectal carcinoma starts with one crypt. The numerous mutations of genes slowly give rise to a small polyp and this then progresses to an invasive carcinoma that eventually metastasizes. The National Polyp Study (NPS) suggested that it took about 10 years for the development of an invasive carcinoma from a “clean” colon in the majority of patients. 4 This lengthy, stepwise natural history provides a window of opportunity for detecting early carcinoma and removing malignant polyps (▶ Fig. 20.1). Thus, screening strategy can be directed toward detecting early carcinoma to reduce morbidity and mortality as well as removing premalignant polyps to reduce the incidence of colorectal carcinoma.
Various screening tests have been shown to achieve accurate detection of early-stage colorectal carcinomas. 5 , 6 , 7 , 8 , 9 Evidence from controlled trials and case–control studies suggests varying degrees of persuasiveness that removing adenomatous polyps reduces the incidence of colorectal carcinoma and detecting early-stage carcinomas reduces mortality from the disease. Finally, screening benefits outweigh its harms. The various ways of screening for colorectal carcinoma all have cost-effectiveness ratios comparable to those of other generally accepted screening tests. 10 , 11 It is important to note that once the screening results are positive, a complete investigation of the entire colon and rectum is mandated to identify colorectal polyps or carcinomas. Screening should be accompanied by efforts to optimize the participation of patients and health care providers, and to remind patients and providers about the need for rescreening at recommended intervals. 12
According to the Centers for Disease Control and Prevention (CDC), only two-thirds of eligible patients in the United States have been screened for colorectal carcinoma. 13 A lack of awareness by the respondent of the need for the test and a lack of recommendation by the physician for the test to be performed were found to be the most commonly reported barriers to undergoing the test. Lack of physician recommendation clearly was an important barrier; among persons who reported undergoing no colorectal carcinoma testing or none recently, only 5% reported that a physician had recommended colorectal carcinoma testing.
Approximately 75% of all new cases of colorectal carcinoma occur in people with no known predisposing factors for the disease. Incidence increases with age, beginning around 40 years. 14 People with no predisposing factors are considered to be at average risk for colorectal carcinoma. People with a family history of colorectal carcinoma (i.e., one or more parents, siblings, or children with the disease) but without any apparent defined genetic syndrome account for most of those at high risk (15–20%). Hereditary nonpolyposis colon cancer (HNPCC) accounts for 4 to 7% of all cases and familial adenomatous polyposis (FAP) about 1%. The remainder, about 1%, are attributed to a variety of uncommon conditions: chronic ulcerative colitis, Crohn’s colitis, Peutz–Jeghers syndrome, and familial juvenile polyposis, in which the colorectal carcinoma risk is elevated but is not as high as in HNPCC and FAP (▶ Fig. 20.2). 10 Other risk factors that should be kept in mind include older age, a diet high in saturated fats and low in fiber, excessive alcohol consumption, and sedentary lifestyle. 15
There is no direct evidence as to when screening should stop, but indirect evidence supports stopping screening in people nearing the end of life. Most polyps take at least 10 years to progress to carcinoma, and screening to detect polyps may not be in the patient’s best interest if he or she is not expected to live at least that long. Also, screening and diagnostic tests are, in general, less well tolerated by elderly people. Therefore, there will come a time in most peoples’ lives when the rigors of screening and diagnostic evaluation of positive tests are no longer justified by the potential to prolong life. The age at which to stop screening depends on the judgment of the individual patient and his or her clinician, taking into account the lead time between screening and its benefits and the patient’s life expectancy. 10
Screening people at average risk for colorectal carcinoma is different from screening people at high risk. Clinicians should determine an individual patient’s risk status well before the earliest potential initiation of screening. The individual’s risk status determines when screening should be initiated, and what tests and frequency are appropriate. 12
Risk stratification can be accomplished by asking several questions aimed at uncovering the risk factors for colorectal cancer. 12 They are as follows:
Has the patient had colorectal carcinoma or an adenomatous polyp?
Does the patient have an illness (e.g., inflammatory bowel disease) that predisposes him or her to colorectal carcinoma?
Has a family member had colorectal carcinoma or an adenomatous polyp? If so, how many? Was it a first-degree relative (parent, sibling, or child), and at what age was the carcinoma or polyp first diagnosed?
A positive response to any of these questions should prompt further efforts to identify and define the specific condition associated with increased risk.
Men and women at average risk should be offered screening with one of the following options beginning at 50 years. A study of a screening colonoscopy in people 40 to 49 years old confirmed that colorectal carcinomas are uncommon in this age group, supporting the recommendation that screening in average risk people begin at age 50 years. 16
The rationale for presenting multiple options is that no single test has unequivocal superiority, and that giving patients a choice allows them to apply personal preferences and may increase the likelihood that screening will occur. However, the strategies are not equal with regard to evidence of effectiveness, magnitude of effectiveness, risk, or up-front costs. Reviewing the rationale section for each screening test below will provide clinicians with information that they can use in presenting the relative effectiveness of each test to patients. These tests are recommended by the American Gastroenterological Association, 12 the American Cancer Society, 17 and the American Society of Colon and Rectal Surgeons guidelines.
20.3 Colorectal Cancer Screening Tests
A number of tests are available and each has advantages and limitations. 12
20.3.1 Stool Testing
Fecal Occult Blood Test
This test offers yearly screening with fecal occult blood test (FOBT) using guaiac-based test with dietary restriction (avoidance of red meat for 3 days prior to performing the test). Two samples from each of three consecutive stools should be examined without rehydration. The patients with a positive test on any specimen should be followed up with colonoscopy. 12 The American Gastroenterological Society recommends yearly testing because it is more effective than screening every 2 years. Rehydration is not recommended. Newer guaiac-based tests are available that have improved sensitivity and appear to maintain acceptable specificity. Dietary restrictions during testing are commonly recommended to reduce the false-positive rate for the more sensitive guaiac-based tests but are not necessary for the less sensitive guaiac-based tests.
With longer (18 years) follow-up in the Minnesota trial, FOBT screening every other year was found to reduce colorectal cancer mortality by 21%, 18 a rate consistent with the results of the biennial screening in the two European trials. 7 The incidence of colorectal carcinoma was also reduced in the screened group. 19 A systematic review of three clinical trials 5 , 6 , 7 , 19 has shown that a restricted diet does not reduce the positivity rate for the older, less sensitive guaiac-based tests and that very restricted diets may reduce compliance rates. 20
Disadvantages of FOBT are that currently available tests for occult blood fail to detect many polyps and some carcinomas. Also, most people who test positive will not have colorectal neoplasia (have a false-positive test result) and, thus, will undergo the discomfort, cost, and risk of colonoscopy without benefit. Colonoscopy is recommended for all those with a positive FOBT because it was a diagnostic procedure used throughout most of the trials and because it is substantially more accurate than double-contrast barium enema (DCBE) for the detection of both small carcinomas and adenomas. 21
Fecal Immunochemical Test
Fecal immunochemical tests (FITs) are more sensitive at detecting both colorectal carcinomas and adenomas than FOBTs. Many FITs require only one or two stool samples, and none require dietary or medication restrictions, increasing ease of use. In 2008, several U.S. professional societies endorsed the use of FITs to replace FOBTs because of the former’s improved performance characteristics and potential for higher participation rates. 22 Countries in Europe and Asia have also adopted widespread colorectal carcinoma screening programs using FITs. 23 However, the diagnostic characteristics of these tests have been difficult to estimate, with reported sensitivities ranging from 25 to 100% for colorectal carcinomas and specificities usually exceeding 90%. 24 A systemic review and meta-analysis of 19 studies found a sensitivity of 79%, a specificity of 95%, and overall accuracy of 96%. 25 Increasing the number of samples did not affect results.
20.3.2 Fecal DNA Testing
Fecal DNA testing is based on the idea that, because carcinoma is a disease of mutations that occur as tissue evolves from normal to adenoma to carcinoma, those mutations should be detectable in stool. 26 Preliminary reports that persons with advanced carcinoma have detectable DNA mutations in stool 27 provided the basis for a large study, using a panel of 21 mutations, in more than 4,000 asymptomatic persons who received screening colonoscopy, fecal DNA testing, and FOBT with Hemoccult II. 28 The DNA marker panel, including mutations in APC, K-ras, and p53, showed a sensitivity of 52% for colorectal carcinoma and specificity of 94%. 29 Such stool-based testing is appealing because it is noninvasive, requires no special colonic preparation, and has the capability of detecting neoplasia throughout the entire length of the colon. 30 Because the DNA alterations in colorectal carcinoma are heterogeneous, assays will need to detect mutations in the number of genes.
The FDA has approved a commercially available test (Cologuard, Exact Sciences, Madison, WI). This is a multitarget stool DNA test consisting of molecular assays for aberrantly methylated BMP3 and NDRG4 promoter regions, mutant KRAS, and β-actin (a reference gene for human DNA quantity), as well as an immunochemical assay for human hemoglobin. Quantitative measurements of each marker are incorporated into a validated, prespecified, logistic-regression algorithm, with a value of 183 or more for a positive test. 29 A 90-site study of over 12,000 patients comparing a stool DNA test to FIT found that the sensitivity of the DNA test for the detection of both colorectal cancer (92.3%) and advanced precancerous lesions (42.4%) exceeded that of FIT by an absolute difference of nearly 20 percentage points. 29 The future of this test will also depend on factors such as the performance characteristics of alternative tests, testing intervals, complications, costs, patient acceptance, and adherence. 30 , 31 , 32
20.3.3 Flexible Sigmoidoscopy
Screening with flexible sigmoidoscopy is recommended every 5 years. Case-controlled studies have reported that sigmoidoscopy was associated with reduced mortality for colorectal carcinoma. 33 , 34 , 35 Colon carcinoma risk in the area beyond the reach of the sigmoidoscope was not reduced. A 5-year interval between screening examinations is a conservative choice. It is supported by the observation that a reduction in colorectal carcinoma deaths related to screening sigmoidoscopy was present up to 10 years from the last screening examination, 33 and that repeat colonoscopy 5 years after a negative colonoscopy found few instances of advanced neoplasia, 36 and follow-up of a cohort of patients after polyp excision showed that development of advanced neoplasia was rare up to 5 years after a negative colonoscopy. 37 The interval is shorter than for colonoscopy because flexible sigmoidoscopy is less sensitive than colonoscopy.
Several studies have shown that the prevalence of proximal advanced adenomas in patients without distal adenomas is in the 2 to 5% range. 38 , 39 , 40 , 41 A flexible sigmoidoscopy followed by colonoscopy if a polyp was found would have identified 70 to 80% of patients with advanced proximal neoplasia. 39 In one randomized controlled trial, screening sigmoidoscopy followed by colonoscopy when polyps were detected was associated with an 80% reduction in colorectal carcinoma incidence. 42
Yearly FOBT combined with flexible sigmoidoscopy every 5 years in a nonrandomized controlled trial reported a 43% reduction (which was not statistically significant) in colorectal carcinoma deaths in people screened with FOBT and sigmoidoscopy relative to sigmoidoscopy alone. 6 The disadvantage of the FOBT/sigmoidoscopy strategy is that people incur the inconvenience, cost, and complications of both tests with an uncertain gain in effectiveness.
20.3.4 Colonoscopy
Colonoscopy is offered every 10 years. Although there are no studies evaluating whether screening colonoscopy alone reduces the incidence or mortality from colorectal carcinoma in people at average risk, several lines of evidence support the effectiveness of screening colonoscopy. 12 There is direct evidence that screening sigmoidoscopy reduces colorectal carcinoma mortality, 33 , 34 and colonoscopy allows more of the large bowel to be examined. Colonoscopy has been shown to reduce the incidence of colorectal carcinoma in two cohort studies of people with adenomatous polyps. 37 , 43 Colonoscopy permits detection and removal of polyps and biopsy of carcinoma throughout the colon. However, colonoscopy involves greater cost, risk, and inconvenience to the patient than other screening tests, and not all examinations visualize the entire colon. The added value of colonoscopy over sigmoidoscopy screening, therefore, involves a tradeoff of incremental benefits and harms. 12
Choice of a 10-year interval between screening examinations for average-risk people (if the preceding examination is negative) is based on estimates of the sensitivity of colonoscopy and the rate at which advanced adenomas develop. The dwell time from the development of adenomatous polyps to transformation into carcinoma is estimated to be at least 10 years on average. 36 , 44
In two large prospective studies of screening colonoscopy, about half of patients with advanced proximal neoplasms had no distal colonic neoplasms. 38 , 39 Similarly, a prospective study of distal colon findings in a cohort of average-risk persons with carcinoma proximal to the splenic flexure found that 65% had no neoplasm distal to the splenic flexure. 45 A randomized controlled trial of sigmoidoscopy with follow-up colonoscopy for all patients with polyps compared with no screening demonstrated a significant reduction in colorectal carcinoma incidence in the screened patients. 41 A cohort of 154 asymptomatic average-risk persons with negative screening colonoscopies had < 1% incidence of advanced neoplasms at a second colonoscopy 5 years later, 35 lending support to the recommended interval of 10 years. Two colonoscopy studies suggested that flat and depressed adenomas account for 22 and 30% of adenomas, 46 , 47 and one report suggests that dye spraying is necessary to not miss these lesions. 46 However, the precise prevalence and clinical significance of flat adenomas is uncertain.
By the end of 2000, the U.S. Medicare system had decided to reimburse for colonoscopy screening. Colonoscopy as the best primary screening test began to be discussed and to be advocated by some gastroenterology organizations. 26
20.3.5 Double-Contrast Barium Enema
This test is recommended every 5 years. The sensitivity of DCBE for large polyps and carcinomas is substantially less than with colonoscopy, the procedure does not permit removal of polyps or biopsy of the carcinomas, and DCBE is more likely than colonoscopy to identify artifacts and other findings (such as stool) as polyps. Patients with an abnormal barium enema need a subsequent colonoscopy.
DCBE is included as an option because it offers an alternative (albeit less sensitive) means to examine the entire colon, it is widely available, and it detects about half of large polyps, which are most likely to be clinically important. Adding flexible sigmoidoscopy to DCBE is not recommended in the screening setting. A 5-year interval between DCBE examinations is recommended because DCBE is less sensitive than colonoscopy in detecting colonic neoplasms.
In a prospective study of DCBE in a surveillance population with a spectrum and prevalence of disease similar to a screened population, DCBE detected 53% of adenomatous polyps 6 to 10 mm in size and 48% of those > 1 cm in size compared with colonoscopy. 31 In a nonrandomized study of 2,193 consecutive colorectal carcinoma cases in community practice, the sensitivity for carcinoma was 85% with DCBE and 95% with colonoscopy. 29
20.3.6 Computed Tomography Colonography (Virtual Colonoscopy)
Computed tomography colonography (CTC) is not currently an option for mass screening for colorectal carcinoma. It is used as a backup for an incomplete colonoscopy, or for patients who are not suitable for a colonoscopy. However, the advances in technology, techniques, and clinical studies have progressed rapidly. It will be just a matter of time before CTC will become another option for colorectal carcinoma screening (see Chapter 3).
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